[Frontiers in Bioscience S4, 581-598, January 1, 2012]
The importance of the multiple target action of green tea polyphenols for neuroprotection
Silvia A. Mandel1, Orly Weinreb1, Tamar Amit1, Moussa B.H. Youdim1
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TABLE OF CONTENTS
1. ABSTRACT
Mounting evidence suggests that lifestyle factors, especially nutrition are essential factor for healthy ageing. However, as a result of the increase in life expectance, neurodegenerative diseases like Alzheimer's and Parkinson's (AD and PD, respectively) are becoming an increasing burden, as aging is their main risk factor. Brain aging and neurodegenerative diseases of the elderly are characterized by oxidative damage, dysregulation of redox metals homeostasis and inflammation. Thus, it is not surprising that a large amount of drugs/agents in therapeutic use for these conditions are antioxidants/metal complexing, bioenergetic and anti-inflammatory agents. Natural plant polyphenols (flavonoids and non-flavonoids) are the most abundant antioxidants in the diet and as such, are ideal nutraceuticals for neutralizing stress-induced free radicals and inflammation. Human epidemiological and new animal data suggest that green and black flavonoids named catechins, may help protecting the aging brain and reduce the incidence of dementia, AD and PD. This review will present salient features of the beneficial multi-pharmacological actions of black and green tea polyphenols in aging and neurodegeneration, and speculate on their potential in drug combination to target distinct pathologies as a therapeutic disease modification approach.
2. INTRODUCTION
Green tea is made from the dried leaves of Camellia sinensis, a small plant grown mainly in China, Japan and Southeast Asia and is consumed in the form of green tea, oolong tea or black tea, all brewed from Camellia sinensis (1). Standing after water, tea signifies the second most frequently consumed beverage worldwide, which varies its status from a simple ancient drink and a cultural tradition to a nutrient endowed with possible neurobiological-pharmacological actions beneficial to human health. The medicinal properties of green tea extract had been attributed to its high content of polyphenolic flavonoids known as catechins. Flavonoids are natural antioxidant substances present in dietary sources from fruits and vegetables and from plant-derived beverages such as pomegranate juice, raspberry, blueberries, red wine and tea. Flavonoids include the subclasses of flavones, isoflavones, flavanols, flavans and flavonols. Catechins are flavanols that are especially concentrated in green tea and account for 30-40% of the dry weight of the leaves (2, 3). Green tea is much richer in catechins than other beverages and compared to black tea, it contains around four times more of the catechin fraction (4). Among the tea catechins, (-)-epigallocatechin-3-gallate (EGCG) is the major constituent, accounting for more than 10% of the extract dry weight; several other polyphenolic compounds found in lower abundance in green tea include (-)-epigallocatechin, (EGC) > (-)-epicatechin (EC) ≥ (-)-epicatechin-3-gallate (ECG) (Figure 1). All four tea catechins have been demonstrated to be potent antioxidants resulting from their direct scavenging of reactive oxygen and nitrogen species (ROS and NOS, respectively), induction of endogenous antioxidant enzymes and the capacity to bind and chelate excess of divalent metals, such as iron and copper (5-7).
Owed to these properties, green tea extract or/and its isolated catechins were tested in a spectrum of neuronal cultures and animal models of neurodegenerative diseases and aging and demonstrated to protect and rescue brain neurons against various exogenous damages (see next sections). Systematic mechanistic studies revealed that the protective contribution of tea catechins relied not only on their known antioxidant/metal chelation activities, but also to their ability to modulate several signal transduction pathways, cell survival/death genes, and mitochondrial function (8, 9). These properties and the reported brain penetrance of some catechins including EGCG (10-12), confer them a multi-target potential to address some of the varied pathologies in aging and neurodegenerative diseases. These include, among others, oxidative stress (OS) damage, dysregulation of redox metals homeostasis, impairment of protein handling and aggregation associated with dysfunction of the ubiquitin-proteasome system (UPS), depletion of endogenous antioxidants, reduced expression of trophic factors, glutamatergic excitotoxicity and inflammation (13-19).
The following sections will elaborate on epidemiological and clinical evidence on the beneficial action of tea flavonoids in aging and neurodegeneration, describe their suggested mechanisms of neuroprotection by simultaneous manipulation of multiple central nervous system targets and discuss a scenario concerning their potential, in drug combination to target distinct pathologies.
3. EPIDEMIOLOGICAL AND CLINICAL STUDIES WITH BLACK AND GREEN TEA IN ALZHEIMER'S AND PARKINSON'S DISEASES
Multiple lines of evidence, mostly from preclinical and epidemiological studies suggest that green tea consumption is associated with reduced risk of severe human malignancies such as cancer, cardiovascular diseases and diabetes, which have been linked to the antioxidant/pro-oxidant properties of its polyphenol constituents (Figure 2) (20-25). In spite of the lack of systematic clinical trials with tea polyphenols in neurodegenerative diseases, the consumption of tea has been suggested to help in supporting the brain as people get older, owing to its high flavonoid (catechin) content. Drinking tea has been found inversely correlated with the incidence of dementia, Alzheimer's disease and Parkinson's disease (AD and PD, respectively). Epidemiological data in elderly Japanese subjects, found that higher consumption of green tea, but not black tea, is associated with lower prevalence of cognitive impairment (26). A recent cross-sectional analysis of participants from the Singapore Longitudinal Ageing Study revealed that regular consumption of black or oolong tea was associated with lower risks of cognitive impairment and decline (27). In the Chinese nonagenarians/centenarians study with 681 participants (67.25% women), men with cognitive impairment had significantly lower prevalence of habits of tea consumption, but significantly higher prevalence of habits of smoking and alcohol consumption (28). Similar outcomes have been found in PD. In the USA, people that consumed 2 cups/day or more of tea presented a decreased risk of PD (29) and a prospective 13-years study of nearly 30,000 finnish adults, demonstrated that drinking 3 or more cups of tea per day is associated with a reduced risk of PD (30). In ~63,000 Asian participants from the prospective Singapore Chinese Health Study followed for 12 years, an inverse association between black tea and PD was found, independent of smoking or caffeine consumption (31). A recent retrospective study with 278 consecutive PD patients reported that consumption of more than 3 cups of tea per day delayed age of motor symptoms onset by 7.7 years and also, smoking ≥10 cigarette packs a year delayed age of PD onset by 3.2 years (32). Regarding clinical studies, a first multicenter, double-blind, randomized, placebo-controlled delayed study to evaluate the safety, tolerability and efficacy of green tea polyphenols in slowing disease progression in patients with early PD, was conducted by the Chinese Parkinson Study Group and supported by The Michael J. Fox Foundation. 410 untreated people with PD were enrolled at 32 Chinese Parkinson Study Group sites. In the first phase of the study participants were randomized to 0.4 g (102 people), 0.8 g (103 people), or 1.2 g (104 people) of green tea polyphenols daily, or placebo (101 people). At 6 months, the placebo group switched to 1.2 g of green tea polyphenols daily for 6 more months (phase 2). If persistent differences are observed between the two groups at the end of phase 2, they cannot be readily explained by effects on symptoms alone, since both groups are receiving the same treatment. Thus, these differences are consistent with the possibility of a disease-modifying effect. A similar rationale has been recently implemented in the ADAGIO (Attenuation of Disease progression with Azilect® Given Once-daily) trial with the anti-PD drug, rasagiline (33, 34). The findings of the Chinese Parkinson Study Group have shown a significant improvement in UPDRS scores at 6 months for patients in each dosage group, yet they were no longer significantly different at 12 months, compared with placebo patient's group (35). The authors concluded that although green tea polyphenols provide a symptomatic benefit in early untreated PD, no obvious disease-modifying effect was seen. A current clinical study with AD is recruiting patients at early stage of AD (MMSE 20-26) for a double blind 18-month clinical trial with Sunphenon, a green tea extract containing 95% EGCG, add-on to Donepezil, in the Early Stage of AD (SUN-AK study, NCT00951834 sponsored by Charite University, Berlin, Germany; completion estimated by April 2011; http://clinicaltrials.gov/ct2/show/NCT00951834). Patients will be prospectively assigned to different EGCG doses and evaluated by ADAS-COG (Score 0-70) as a primary outcome. Sunphenon has previously been shown by the authors to exert an excellent tolerability in an 18-month clinical period. However, clinical evidence demonstrating that green tea and other antioxidant polyphenols can act as protective drugs in neurodegenerative diseases is still relatively scarce, emphasizing the need of well-designed controlled studies to assess a risk reduction of PD and AD in consumers of green and black tea.
4. NEUROPROTECTIVE STUDIES WITH GREEN TEA
4.1. Preclinical in vivo data in aging and neurodegeneration models
Animal studies with green tea extract polyphenol fraction or its individual catechin components, have shown positive effects on cognitive and behavioral abilities during aging and in neurodegenerative conditions (9, 36). In particular, these studies have enabled to unravel the molecular mechanisms and survival pathways behind the effects of tea catechins on brain function and cognition. Research on aging has shown that 6 months administration of the antioxidant cocktail drink, β-catechin or a green tea catechin fraction, extended the mean lifespan of senescence-accelerated mouse prone-8 (SAM-P8), (37, 38) and C57BL/6 J mice (39). In old Wistar rats, green tea catechins prevented the spatial learning and memory decline after 7 months of treatment, seemingly due to the reduction of OS-related damage (40). Studies using the main green tea catechin constituent, EGCG have documented an attenuation of cognitive deficits, antioxidant enzymes decline and apoptotic parameters in D-galactose- induced mice aging (41) and significant longevity-extending effects in Caenorhabditis elegans under stress (42). EGCG has been also shown to improve age-related cognitive decline and protect against cerebral ischemia/reperfusion injuries (43, 44), brain inflammation and neuronal damage in experimental autoimmune encephalomyelitis (EAE)(45). Recently, EGCG administration was shown to reduce the brain infarct volume of mice after transient focal ischemia accompanied by a reduction of metalloproteinase (MMP)-9 activity (46).
The positive neuroprotective effects of green tea and EGCG have been also documented in various models of neurodegenerative diseases; EGCG treatment significantly prolonged the symptom onset and life span and attenuated death signals in ALS mice model with the human G93A mutated Cu/Zn-superoxide dismutase (SOD1) gene (47). Similarly, a green tea polyphenol extract or individual EGCG, prevented striatal dopamine (DA) depletion and SN pars compacta (SNpc) dopaminergic neurons loss when given chronically to mice or rats treated with the parkinsonism-inducing neurotoxins, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 6-hydroxydopamine (6-OHDA), respectively (48, 49). These findings receive further support from our recent animal studies, where EGCG given post-damage was shown to almost completely restore nigrostriatal DA neuron degeneration caused by MPTP (50). In terms of cognition-impaired models, long-term administration of a preparate of green tea catechins (Polyphenol E), was demonstrated to improve spatial cognition learning ability in naïve rats and prevent cognitive deficits in intracerebral amyloid beta peptide (Ab)-damaged rats (51, 52). Additionally, EGCG reduced cognitive dysfunction in Ab-injected mice (53) and prevented cerebral amyloidosis and impaired cognition in Alzheimer's transgenic mice (54, 55). In lipopolysaccharide-mediated neuroinflammation, oral treatment with EGCG prevented neuronal cell death and memory impairment of mice and inhibited Aβ1-42 generation, possibly through inhibition of β- and g -secretase (56). These findings suggest that EGCG could be a useful agent in Aβ-induced cognitive impairement and brain pathology. In a mouse model for HIV-related dementia, EGCG was found to mitigate neurotoxicity mediated by HIV-1 proteins gp120 and Tat in the presence of interferon (IFN)-gamma (57). More recently, in the 3-nitropropionic acid rat model of Huntington disease with manifest excitotoxicity and striatal degeneration, EGCG significantly attenuated behavioral alterations, oxidative damage, mitochondrial complex enzymes dysfunction and striatal damage (58).
4.2 Preclinical cell culture studies
In line with the in vivo findings, cell culture studies have demonstrated that flavanol catechin reduced damage produced by hydrogen peroxide, 4-hydroxynonenal, rotenone and 6-OHDA in primary rat mesencephalic cultures, as shown by increases in cellular viability and (3H)DA uptake (59). In human neuroblastoma (NB) SH-SY5Y cells, EGCG prevented neuronal cell death caused by the neurotoxins 6-OHDA and 1-methyl-4-phenylpyridinium (MPP+) (60) and protected primary hippocampal neurons (61) and rat pheochromocytoma (PC12) cells (62) from Aβ-induced toxicity. More recently, both catechin and epicatechin were shown to protect cultured rat cortical neurons against Aβ (25-35)-induced neurotoxicity through inhibition of cytosolic calcium elevation (63). In addition, recent studies from our laboratory have demonstrated that EGCG is able to rescue and reduce mortality of NB SH-SY5Y cells when given up to 3 days after long-term serum starvation, a progressive model of apoptotic damage (64). Complementary large-scale proteomic analysis demonstrated that EGCG induced the differential expression of three major clusters of proteins related to the cytoskeleton (e.g. beta tubulin IV and tropomyosin 3), heat shock (e.g. 14-3-3 gamma, heat shock protein gp96) and metabolic energy (e.g. ATP synthase H+ transporting, mitochondrial F1 complex beta, glucosidase II beta and nerve vascular growth factor (VGF) inducible precursor) (65, 66).
5. MECHANISM OF NEUROPROTECTIVE ACTION OF GREEN TEA POLYPHENOLS
Tea catechins/flavanols are presently considered multifunctional and multitarget compounds invoking pleiotropic effects on numerous biological pathways to help keep human brain cells from dying and even help repair them. The following sections will describe salient pharmacological actions and molecular targets underlying their health benefits.
5.1 Iron chelation and antioxidant activity
There is increasing evidence that iron is involved in the mechanisms that underlie many neurodegenerative diseases (67, 68). Non-haem iron (mostly in complex with ferritin) progressively accumulates particularly in regions that are affected by AD and PD such as the putamen, motor cortex, prefrontal cortex, sensory cortex and thalamus during the first 30-35 years of life, and variable changes are observed in older individuals (67, 69). Also, during brain ageing iron is partially converted from its stable and soluble form with ferritin into haemosiderin, a partially proteolytic product of ferritin that contains iron at higher reactivity thereby increasing the risk of OS (70). Owing to its interaction with hydrogen peroxide (partly derived from excessive monoamine oxidase (MAO)-B activity in aging, AD and PD(71-73)) through Fenton chemistry, Fe2+enhances generation of ROS which in turn can increase protein aggregation, including the aggregation of alpha-synuclein and Aβ, two major contributors of PD and AD pathology, respectively (Figure 3). Analysis of PD and AD brains indicates iron accumulation within specific brain regions displaying selective vulnerability to neurodegeneration, such as the substantia nigra (SN), hippocampus and cerebral cortex (74-76) in association with both intraneuronal neurofibrillary tangles (NFT), composed of hyperphosphorylated microtubule-associated protein tau (PHFt) and Ab-containing extraneuronal senile plaques.
The apparent link between metal dishomeostasis and neurodegenerative diseases has given rise to the conception of metal chelation therapy as a therapeutic option. In fact, a number of iron chelators/antioxidants have been shown to possess neuroprotective activity in animal models of neurodegeneration (77-82). Plant flavonoids are potent chelators of transitional metals, such as iron and copper owed to the OH at position 3 of the C ring, the OH at positions 3' and 4' of the B ring, or the three OH groups present in the gallol moiety of some polyphenols such as EGCG and ECG (Figure 1) (7, 83-85). In a recent study examining the differential potency of a series of polyphenols (e.g (-)-epicatechin, vanillic acid, gallic acid, quercetin, myricetin) to prevent DNA damage caused by Fe2+ and H2O2, it was found that of the 12 phenolic compounds tested, EGCG was the most potent, inhibiting over 90% of the iron-mediated DNA break (85). By correlating the pKa and IC50 values of phenolic compounds for inhibition of Fe2+/H2O2 -induced neurotoxicity, the same group (86) suggested that the binding of the polyphenols to iron was essential for their antioxidant activity.
It seems plausible that green tea polyphenols may be beneficial in aging and for treatment of PD and AD, where OS and accumulation of iron at brain areas associated with neurodegeneration have been shown (17, 18, 67, 87, 88). Tea catechins are phenolic compounds and as such, they act as powerful hydrogen-donating radical scavengers of ROS and RNS and possess the ability to chelate transition divalent metal ions (Cu2+, Zn2+, Fe2+), thereby preventing the formation of iron-induced free radicals in in vitro and cell/tissue systems (7, 89). In brain tissue, green tea and black tea extracts were shown to strongly inhibit propagatory chain reaction of lipid peroxidation promoted by iron-ascorbate in homogenates of brain mitochondrial membranes (90). A similar effect was also reported using brain synaptosomes, in which the four major polyphenol catechins of green tea were shown to inhibit iron-induced lipid peroxidation (6). In the majority of these studies, EGCG was shown to be more efficient as a radical scavenger than its counterparts ECG, EC and EGC, which might be attributed to the presence of the trihydroxyl group on the B ring and the gallate moiety esterified at the 3' position in the C ring (7).
It is suggested that in vivo, the neuroprotective effect of green tea polyphenols may involve the regulation of antioxidant protective enzymes. Thus, EGCG was found to elevate the activity of two major oxygen-radical species metabolizing enzymes, superoxide dismutase (SOD) and catalase in mice striatum (48). Oral administration of green tea extracts to young rats or EGCG to aged rats exhibited higher levels of antioxidant enzymes, such as glutathione peroxidase, reductase, SOD and catalase in whole brain homogenates (91, 92) and hippocampal tissue (93), compared to their respective controls. Other contribution to ROS production stems from elevated MAO-B enzyme activity. Indeed, EGCG was shown to inhibit MAO-B activity in adult rat brains (94) and C6 astrocyte cells (95). Moreover, a recent study demonstrated inhibition of nitric oxide synthase, an important ROS-generating enzyme, in the SN and striatum of MPTP mice model of PD (96). Furthermore, in peripheral tissue, it has been shown that a number of flavonoids and phenolic antioxidants at low concentrations, activate the expression of some stress-response genes, such as phase II drug metabolizing enzymes, glutathione-s-transferase and heme oxygenase-1 (HO-1), in correlation with an increase in the activity and nuclear binding of the transcription factors Nrf1 and Nrf2 to the antioxidant regulatory element (ARE) sequences contained in their promoters (97, 98).
5.1.1. Attenuation of Aβ, hyperphosphorylated τ and alpha-synuclein aggregation
The use of non-toxic, naturally occurring neuroprotective and metal-complexing flavonoids with brain access could, in theory, ''pull out iron'' from those brain areas where it preferentially accumulates and alleviate the brain from free-reactive iron overload by directly influencing aggregation and deposition of Aβ and alpha-synuclein in brains of AD and PD patients, respectively. Iron was demonstrated to facilitate the aggregation of Aβ and induce aggregation of the major constituent of NFTs, hyperphosphorylated τ (Tau) (99, 100). In vitro studies demonstrated that Aβ has high affinity for iron, and the iron-binding sites are located in the hydrophilic N-terminal part of the peptide (101). When neuronal cells were exposed to Aβ in the presence of the iron chelator desferroxamine, toxicity was significantly attenuated, while conversely, the toxicity was restored to original levels following incubation of Aβ with excess free iron (102), suggesting a redox-active iron-mediated effect. Similarly to Aβ, alpha-synuclein has been shown to form toxic aggregates in the presence of iron and this is considered to contribute to the formation of Lewy body via OS, being one of its constituents(103, 104).
In addition to the attenuation of iron- and OS-mediated peptide aggregation, natural flavonoids were shown to bind directly to Aβ and alpha-synuclein nascent fibrils or mature aggregates and impair their stability. Indeed, wine polyphenols (e.g., resveratrol, myricetin, quercetin, kaemferol), curcumin, (+)-catechin, (-)-epicatechin, nordihydroguaiaretic acid, and rosmarinic acid, were shown to inhibit formation of nascent Ab and alpha-synuclein fibrils, elongation of the fibrils, and destabilization of the formed assemblies (105, 106). EGCG was reported to interfere with an early step in the amyloid formation cascade by binding directly to the natively unfolded alpha-synuclein and Ab polypeptides, thus inhibiting their fibrillogenesis and redirecting them into an alternative "off pathway" before they become toxic (Figure 3) (107). A similar effect was observed with resveratrol (108). In effect, partial aggregated and oligomerized intracellular Aβ was documented to be cytotoxic and synaptotoxic in cell culture and impair memory in animal studies (109). Similarly, a truncated form of alpha-synuclein showed increased aggregation into large inclusions bodies, increased accumulation of high molecular weight alpha-synuclein species, and enhanced neurotoxicity in transgenic Drosophila (110).
In addition to its early effect on Aβ and alpha-synuclein fibrillogenesis, EGCG was lately shown to convert large, mature alpha-synuclein and Aβ fibrils into smaller, amorphous non-toxic protein aggregates and this effect was evident only with catechins carrying a gallate moiety such as ECG and EGCG (111), the group in the molecule suggested to complex iron. Thus, it is possible that the direct binding of iron-complexing flavonoids to Aβ via the gallate group, plays a major role in the disruption and solubilization of the plaques in AD animal model and in vitro aggregates. In this regard, another study showed that only gallate forms of catechins were able to protect hippocampal cells against amyloid-induced toxicity (112).
5.1.2. Inhibition of amyloid precursor protein (APP) translation
Another outcome of transition metal-complexing molecules, including EGCG, is related to their ability to reduce Aβ; formation via translational suppression of its generator, amyloid precursor protein (APP), a type I integral membrane protein. This effect is associated with modulation of an iron responsive element (IRE) located at APP 5'UTR-mRNA (113, 114). In mouse hippocampus, EGCG was shown to down-regulate membrane-associated APP protein level (115). In SH-SY5Y cells EGCG reduced full-length APP, without altering APP mRNA levels, while exogenous iron supplementation reversed its effect (113). These results suggest a post-transcriptional action, presumably by the mechanism of chelating intracellular iron pools and APP mRNA post-transcriptional inhibition (Figure 3). This is further supported by the observation that EGCG suppressed translation of a luciferase reporter gene driven by the IRE-type II-containing sequences of APP (113). Furthermore, it was found that EGCG markedly reduced secreted Aβ levels in the conditioned medium of Chinese hamster ovarian cells, overexpressing "Swedish" mutated APP (CHO/ΔNL) (113) and in primary neuronal cells derived from transgenic mice bearing the APP "Swedish" mutation (54). Recently, Friedlich et al (116) have described a putative IRE in the 5'-UTR of PD-related alpha-synuclein mRNA and predicted that this RNA structure may have the potential to function as a post-transcriptional regulator of α alpha-synuclein protein synthesis in response to iron and redox events, in a pattern that resembles that of APP and the iron-associated protein ferritin (67, 114).
5.1.3. Modulation of iron-dependent hypoxia-inducible factor-1
An additional level of neuroprotection by iron-complexing agents involves the stabilization of the transcriptional activator, hypoxia-inducible factor (HIF)-1 and expression of its target protective genes, such as erythropoietin, vascular endothelial growth factor (VEGF), enolase, transferrin receptor and heme oxygenase. HIF-1 is a heterodimeric transcription factor, composed of two subunits: HIF-1α, an oxygen-labile protein that becomes stabilized under hypoxic conditions and HIF-1β, which is constantly expressed (117). HIF is highly involved in the pathology of a number of diseases associated with tissue hypoxia (reduced oxygen tension) (118). Within the cells, HIF-1 is under the control of a class of iron-dependent and oxygen-sensor enzymes, HIF prolyl-4-hydroxylases (PHDs) that target the regulatory alpha subunit of HIF-1 for degradation by the proteasome (117) (Figure 3). The possibility of modulating HIF-1 activity by targeting the free-labile intracellular iron pool by iron chelators and inhibitors of PHDs is gaining recognition, posing HIF-1 as a potential therapeutic target for neurodegenerative diseases (119-121). Similar to hypoxia, natural flavonoids were demonstrated to induce intracellular accumulation of HIF-1α through activation of enzyme systems and signaling pathways, such as phosphatidylinositide 3'-OH kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK, e.g. extracellular signal-regulated protein kinase, (ERK)), as well as by a direct complexing of iron and inactivation of PHDs (84, 122-124). For example, the main constituent of the standardized dietary flavone, Ginkgo biloba (Ginkgoaceae) extract, EGb 761, was demonstrated to protect hypoxic PC12 cells and up-regulate HIF-1 α protein expression through the activation of the p42/p44 MAPK pathway(125). Studies with different cell lines demonstrated that a number of flavonoids including luteolin, fisetin and quercetin, induced HIF-1α levels under normal oxygen pressure and this effect was structurally related to the capability of the molecules to efficiently bind intracellular iron (124, 126, 127). Also, EGCG and ECG were shown to induce HIF-α protein and HIF-1 activity and increase the mRNA expression levels of its pro-survival gene targets glucose transporter-1 (GLUT-1), VEGF, and p21waf1/cip1, whereas this effect was blocked by iron and ascorbate, indicating that these catechins may activate HIF-1 through the chelation of iron (128, 129). Similar results were reported for the flavonoid quercetin(84).
Another link between hypoxia and iron is reflected by the hypoxic-mediated positive regulation of two ubiquitously expressed, homologous members of the aconitase gene family, the iron regulatory proteins (IRPs), IRP1 and IRP2 (130) and consequential transactivation or inhibition of their target mRNAs, such as AβPP, transferrin receptor, ferritin and ferroportin. The mRNA binding activity of IRP2 is regulated at the level of protein abundance, through iron dependent degradation by the ubiquitin-proteasome pathway. This degradation is also facilitated by oxygen. Thus, at low cellular iron and oxygen levels, IRP2 is stabilized and able to bind IREs on target mRNAs (131). Interestingly, the free iron-induced proteasomal-mediated degradation of IRP2 involves also activation of a PHD and is inhibited by iron chelators (132, 133). Thus, it is possible that IRP2 and HIF-1 protein abundance is modulated by a common pathway. The reduction in the chelatable iron pool by EGCG may result in the inhibition of PHD activity and consequently, in the concerted activation of both HIF and IRP2.
5.2. Modulation of cell signaling pathways by green tea polyphenols
Originally viewed as simple antioxidants/anti-inflammatory, plant-derived flavonoids including the main flavanol polyphenol of green tea, EGCG are currently suggested to selectively activate kinase signaling molecular pathways implicated in neuronal plasticity, regeneration and survival. It cannot be ruled out, however, that some of these effects may have resulted from interplay between their scavenging/neutralization action of ROS/NOS and consequential attenuation/induction of related signal transduction pathways.
5.2.1. Activation of the protein kinase C (PKC) pathway
Our previous in vitro cell signaling studies revealed a specific involvement of the PKC pathway in the neuroprotective mechanistic action of EGCG (60, 134). PKC has a fundamental role in the regulation of cell survival, programmed cell death, long-term potentiation (LTP) (135) and consolidation of different types of memory (136, 137). Additionally, the induction of PKC activity in neurons has been shown to protect against various exogenous insults, such as oxygen/glucose deprivation in organotypic slice cultures (138) or Aβ toxicity in rat cortical or hippocampal neurons (139, 140).
A more direct demonstration of a possible interaction between green tea catechins and PKC has been provided by the study of Kumazawa et al (141) employing solid-state nuclear magnetic resonance and showing that EGCG interacts with the head group region of the phospholipids within lipid bilayers from liposomes and moves freely on the membrane surface (142). The interaction pattern of EGCG in terms of rotational motion within the lipid bilayers was similar to that described for the phorbol ester 12- O -tetradecanoylphorbol-13-acetate (TPA) (143), a prototype activator of PKC. This suggests that a direct interaction of green tea catechins with cell membranes may result in the rapid PKC activation shown previously by our group (60) (Figure 3). Furthermore, the impact of EGCG on membrane fluidity may give rise to activation of other membrane-associated signaling pathways.
The distinct activation of PKC isoforms/pathway has been recently reported also for curcumin, the natural phytochemical obtained from dried root of Turmeric (Curcuma Longa), which was shown to compete with Ca2+ for the regulatory domain of PKC (144). Fluorescence spectroscopy and molecular modeling studies found that curcumin binds to the N-terminal region of PKCδ, PKCε and PKCθ with an EC50 and fluorescence emission similar to that of TPA (145).
The following sub-sections will present topical literature on the involvement of PKC signaling system in the modulation of apoptotic molecular mediators, mitochondria integrity, APP processing and DA synaptic function by polyphenols.
5.2.1.1 Prevention of apoptosis and mitochondrial dysfunction
The antiapoptotic/neuroprotective actions of green tea catechins seem to be attained at low micromolar concentrations, whereas high doses have been shown to exert anti-proliferative, anti-angiogenic and pro-apoptotic actions, thus having implications in cancer management (60, 146). A rapid phosphorylative activation of PKC by low micromolar concentrations of EGCG is thought to be the main mechanism accounting for its neuroprotective activity against several neurotoxins, such as Aβ (147), serum withdrawal (62, 64), and 6-OHDA (60) and for its neurorescue effect against long-term growth factors withdrawal (64). The neurorestorative effect was demonstrated to involve reduction of the apoptotic markers, cleaved caspase 3; its downstream cleaved substrate poly-ADP-ribose-polymerase (PARP), a nuclear zinc finger DNA-binding protein that detects and binds to DNA strand breaks; Bad, a member of a group of "BH3 domain only" proteins of the Bcl-2 family (64). This was accompanied by a rapid translocation of the isoform PKCα (particularly important in neuronal growth and differentiation in the brain), to the neuronal membrane compartment (64, 148). Accordingly, upon pharmacological inhibition of PKC activity, EGCG could not overcome the neuronal death, suggesting that this cascade is essential for the neuroprotective and neurorescue effects of EGCG. In vivo, it was also shown that a 2 weeks treatment of naïve with EGCG prevented the extensive depletion of PKCα and counteracted the robust increase of pro-apoptotic Bax protein in the striatum and SN of mice intoxicated with MPTP (149). Similarly, a particular involvement of PKC activity was shown for the wine polyphenol, resveratrol against Aß toxicity in hippocampal neurons, while PI3K or MAP kinases signaling pathways were not activated by the polyphenol (140).
Recently, we have identified a novel PKC-linked pathway in the neuroprotective mechanism of action of EGCG, which involves a rapid PKC-mediated degradation of Bad protein by the UPS in NB SH-SY5Y cells (134). Bad has been suggested to link survival signals to the mitochondrial cell death machinery. It may directly contribute to the opening of the mitochondrial megachannel permeability transition pore by its heterodimerization with the mitochondrial death suppressor proteins Bcl-2 and/or Bcl-xL, thus neutralizing their antiapoptotic function (150). In this respect, one month administration of EGCG (2 mg/kg) to aged (> 24 months) male Wistar rats augmented the activities of Kreb's cycle enzymes and electron transport chain complexes in brain mitochondria, decreased the expression of hydroxynonenal in aged brain, and up-regulated the antioxidant system (151). These results support an antioxidant potential of EGCG at the level of mitochondria. Indeed, a recent study suggests that EGCG could directly scavenge mitochondrial generated free radicals, as it was found to accumulate in mitochondria and selectively protect rat cerebellar granule neurons from apoptosis induced by various generators of OS (152). This may partly account for the attenuation of depolarization of the inner mitochondrial membrane potential by a polyphenol-rich green tea extract or EGCG, following oxygen-glucose deprivation in C6 glial culture (153).
5.2.1.2. Regulation of APP and DA metabolism
APP can be processed via alternative pathways: a non-amyloidogenic secretory pathway that includes cleavage of APP to sAPPa by a putative a-secretase within the sequence of the amyloidogenic Ab peptide, thus precluding the formation of Ab; the second pathway generates Ab via the sequential action of b- and g-secretases (154). Previous studies have demonstrated that either short- or long-term incubation with EGCG promotes the generation of the non-amyloigogenic, soluble form of APP, sAPPa, via PKC-dependent activation of a-secretase (113, 147). In contrast to Ab, sAPPa possesses neuroprotective activities (155) and promotes neurite outgrowth (156) and synaptogenesis (157). Since sAPPa and Ab are formed by two mutually exclusive mechanisms, it can be assumed that stimulation of the secretory processing of sAPPa might prevent the formation of the amyloidogenic Ab (Figure 3). New supportive data emerged from a study conducted in an Alzheimer's transgenic mice model, showing that EGCG promotes sAPPa generation through activation of a-secretase cleavage (54) (158). This was accompanied by a significant reduction in cerebral Ab levels and b-amyloid plaques. These results were supported in vitro by the observation that exogenously added EGCG to primary neurons derived from the above transgenic mice bearing the APP "Swedish" mutation, markedly reduced secreted Ab levels in the conditioned medium (54). More recently this research group reported that encapsulation of EGCG into nanolipidic particles markedly improved its neuronal α-secretase enhancing ability in vitro and its oral bioavailability in vivo over free EGCG (159).
Other potential beneficial effect of PKC activation in AD is related to the recent finding showing that neuronal overexpression of PKCe in transgenic mice expressing familial AD-mutant forms of the human APP, decreases Ab levels and plaque burden and this is accompanied by increased activity of endothelin-converting enzyme (ECE), which degrades Ab (160). Thus, it can be hypothesized that since EGCG has been shown to increase the levels of PKC isoforms a and e in mice hippocampus and striatum (147, 149), EGCG may reduce Ab levels in AD pathology, both via concomitant stimulation of sAPPa secretion and promotion of Ab clearance through increased ECE activity (Figure 3). Despite the general support for the amyloid hypothesis as a key contributor to neuronal death and dementia in AD, a direct connection between Ab deposits in senile plaques and neurodegeneration has not been yet established. In this respect, Alzheimer's transgenic mice with Ab deposits do not exhibit significant neuronal loss in hippocampus and association cortex (161). Therefore, the ultimate proof for the effectiveness of drugs, capable of lowering or eliminating brain Ab aggregation/accumulation will be their clinical benefit.
PKC-dependent pathway activation was also implicated in the regulatory effect of EGCG on DA presynaptic transporters (DAT) internalization (162). EGCG caused a dose-dependent inhibition of DA uptake in DAT-PC12 and decreased membrane-bound DAT, while this effect was abolished by blockade of the PKC pathway This observation, together with the finding that EGCG inhibited catechol-O-methyltransferase (COMT) activity in rat liver cytosol homogenates (163), may be of particular significance for PD patients given that DA and related catecholamines are physiological substrates of COMT.
5.2.2 Modulation of other Signal Transduction Pathways
In addition to PKC, other cell signaling pathways have been implicated in the action of green tea catechins, such as mitogen activated protein kinase (MAPK, e.g. ERK1 and 2) and PI3K/AKT signaling cascades (36, 115), known to be connected to attenuation of neuronal death and cellular injury by OS (164-166) (Figure 3). Previous in vitro studies demonstrated the potency of EGCG to induce antioxidant responsive element (ARE)-carrying stress genes, such as phase II drug metabolizing enzymes, glutathione-s-transferase and heme-oxygenase1, likely via activation of the MAPK pathway cell survival signaling regulators, as p44/42 ERK 1/2, JNK and p38 MAPK (97, 167). Thus, green tea catechins may activate MAPK signaling cascades to normalize ERK activity caused by exogenous OS-inducing agents. Indeed, it was shown that EGCG counteracted the decline in ERK1/2 induced by 6-OHDA in NB SH-SY5Y cells (60) and induced phosphorylation of ERK1/2 in serum-deprived SH-SY5Y cells (65). In rat cortical neurons, the flavanol (-)epicatechin induced a concentration-dependent phosphorylation of PI3-K, ERK1/2 and their downstream substrate, cAMP responsive element binding protein (CREB) and subsequently increased CREB-regulated gene expression (146). CREB is a transcription factor that binds to the promoter regions of many genes associated with memory and synaptic plasticity, playing a crucial role in long-term potentiation (LTP) and long-term memory formation (168, 169). In agreement with the in vitro findings, chronic treatment of two different strains of aged mice with green tea catechins promoted improvement in learning tasks and memory deficits, associated with increased levels of CREB phosphorylation in the hippocampus and increased expressions of brain-derived neurotrophic factor (BDNF) and Bcl-2, two target genes of CREB, having regulatory roles in synaptic plasticity (38, 39). Similar gene alterations were recently reported in hippocampus of old rats after prolonged administrations of green tea infusion (93). Also, 5 weeks oral administration of l-Theanine, an amino acid component of green tea to mice, was reported to attenuate cognitive dysfunction and neurotoxicity induced by intracerebroventricular injection of Aβ1-42 via inhibition of MAPK/p38 and the inflammatory nuclear factor κB (NF-κB) pathways (170).
6. COMBINATION THERAPY WITH GREEN TEA POLYPHENOLS TARGETING DISTINCT BRAIN PATHOLOGIES
The poly-etiological origin of AD and PD, suggests that the ability to modulate several targets at once could be beneficial for these diseases. This has laid the basis for the assumption that a single drug possessing two or more active neuroprotective moieties, or a combination of compounds, targeted at multiple pathological aspects of the same disease, may offer a superior therapeutic benefit. In line with this rationale, current therapeutic strategies in neurodegenerative diseases entail combination of available drugs in the market ((e.g. acetyl cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) antagonist in AD; levodopa and dopaminergic agonist in PD)) and addition of nutritional supplements to the diet such as antioxidant vitamins, CoQ10, fish oil, EGCG-enriched capsules, folate, vitamin B6, alpha-tocopherol, S-adenosyl methionine, N-acetyl cysteine, acetyl-L-carnitine and ginko biloba extracts together with changes in lifestyle and behavior (171-177).
Following this therapeutic strategy rationale, we have recently selected the anti-PD drug, rasagiline (Azilect®), a second generation, irreversible selective inhibitor of MAO-B and EGCG for an in vivo preclinical neurorescue/neurorestorative drug cocktail study. Mounting evidence from preclinical, epidemiologic and human clinical trials, indicates that both compounds exert a neuroprotective action (26, 29-32, 34, 48, 178-182). The underlying principle was that the distinct neuroprotective/neurorescue pharmacological profile of rasagiline would complement that of EGCG and restore the neuronal loss and molecular targets damaged in animal parkinsonism. Our results revealed that subliminal doses of rasagiline and EGCG, which individually have no profound protective effect, synergistically restored DA neurons in the SNpc and replenished SNpc serine/threonine kinase Akt/PKB levels and striatal DA, when given to mice after MPTP lesion(50). In analogy to PD, a recent study conducted in Tg2576 mice model of AD showed that co-treatment with the nutritional supplements fish oil (8mg/kg/day) and EGCG (12.5mg/kg/day) synergistically inhibited cerebral Aβ deposits (183). Similarly, in the triple transgenic mice model of AD (βAPPSwe, presenilin-1M146V and tauP301L) dietary treatment with fish oil/omega-3 fatty acids, curcumin, or a combination of both has the potential to improve insulin/trophic factor pathway defects, (increased phospho-insulin receptor substrate-1 IRS-1 and decreased total IRS-1) and cognitive deficits that are observed in AD (184). Also, a nutraceutical combination of polyphenols from blueberry and green tea, the amino acid carnosine and vitamin D3, has been shown to improve neural stem cell proliferation in the subventricular zone in aged rats and cognitive function in aged rats (185). In a mouse excitotoxic injury model a combination of tea polyphenol and memantine (an NMDA receptor antagonist), but not each compound alone, improved the impaired locomotor activity (50, 182).
This further support the view that moderate diet supplementation with nutritional additives could be of significant therapeutic value for the treatment of aging, neurodegenerative diseases and clinical excitotoxic injury such as brain trauma, brain ischemia and epilepsy.
7. PERSPECTIVE
The comprehension of the health beneficial effects of diets rich in fruits and vegetables could contribute to a healthier aging process and decreased prevalence of cognitive deficits and common neurodegenerative diseases. Possibly, the daily intake of dietary plant flavonoids will constitute a prophylactic treatment long before the onset of symptoms in people at risk of getting AD, PD or other neurological diseases with neuronal degeneration (family history, genetic predisposition) and to delay the cognitive decline and other deterioration processes in aging.
It becomes evident that neurodegenerative disorders will require multiple target therapy to address the varied pathological aspects of the disease. Thus, it is not surprising that a large amount of drugs/agents in therapeutic use for these conditions are antioxidants/metal complexing, bioenergetic and anti-inflammatory agents. Therefore, the multi-pharmacological activities of green tea catechins, added to their non-toxic, brain permeable lipophilic nature may be of significance for neuroprotection/neurorescue. Presently, their suggested potential cellular sites of action include a direct neutralization of free-radicals induced OS, attenuation of reactive free-iron pool and consequent reduction in APP/alpha-synuclein translation, modulation of the activity of endogenous antioxidant detoxifying enzymes, pro-survival protein kinases, metal and calcium homeostasis, transcription factor(s) activation, mitochondrial integrity and promotion of neurite outgrowth. It is plausible that some of the actions result from a common effect of green tea polyphenols on one or more of the kinases and/or their upstream activators.
An additional novel approach entails drug combination or poly-pharmacology, providing a practical way to design specific neuroprotective therapy. The complex symptomatology of neurodegenerative diseases often necessitates the use of more than one drug (monotherapy). New emerging preclinical evidence suggest that in a combination therapy regime, green tea EGCG may have the potential to complement the pharmacological activities of current drugs in use for neurodegenerative diseases, such as rasagiline and memantine (50, 182). These findings underline the importance of having a clear understanding of green tea catechins molecular mechanism of action, in the evaluation of its potential in a polypharmacy paradigm, with drugs possessing distinct neuroprotective pharmacological profile, in the quest for a disease modifying therapy.
8. REFERENCES
1. H. N. Graham: Green tea composition, consumption, and polyphenol chemistry. Prev Med, 21(3), 334-50 (1992) doi:10.1016/0091-7435(92)90041-F
2. Z. Y. Wang, M. T. Huang, Y. R. Lou, J. G. Xie, K. R. Reuhl, H. L. Newmark, C. T. Ho, C. S. Yang and A. H. Conney: Inhibitory effects of black tea, green tea, decaffeinated black tea, and decaffeinated green tea on ultraviolet B light-induced skin carcinogenesis in 7,12-dimethylbenz(a)anthracene-initiated SKH-1 mice. Cancer Res, 54(13), 3428-3455 begin_of_the_skype_highlighting
(1994) PMid: 8012962
3. C. S. Yang and Z. Y. Wang: Tea and cancer. J Natl Cancer Inst, 85(13), 1038-49. (1993)
doi:10.1093/jnci/85.13.1038
4. S. Khokhar and S. G. Magnusdottir: Total phenol, catechin, and caffeine contents of teas commonly consumed in the United kingdom. J Agric Food Chem, 50(3), 565-70 (2002)
doi:10.1021/jf010153l
PMid:11804530
5. A. S. Pannala, C. A. Rice-Evans, B. Halliwell and S. Singh: Inhibition of peroxynitrite-mediated tyrosine nitration by catechin polyphenols. Biochem Biophys Res Commun, 232(1), 164-8 (1997)
doi:10.1006/bbrc.1997.6254
PMid:9125123
6. Q. Guo, B. Zhao, M. Li, S. Shen and W. Xin: Studies on protective mechanisms of four components of green tea polyphenols against lipid peroxidation in synaptosomes. Biochim Biophys Acta, 1304(3), 210-222 (1996)
PMid:8982267
7. F. Nanjo, K. Goto, R. Seto, M. Suzuki, M. Sakai and Y. Hara: Scavenging effects of tea catechins and their derivatives on 1,1-diphenyl-2-picrylhydrazyl radical. Free Radic Biol Med, 21(6), 895-902 (1996)
doi:10.1016/0891-5849(96)00237-7
8. T. Amit, Y. Avramovich-Tirosh, M. B. Youdim and S. Mandel: Targeting multiple Alzheimer's disease etiologies with multimodal neuroprotective and neurorestorative iron chelators. Faseb J, 22(5), 1296-305 (2008)
doi:10.1096/fj.07-8627rev
PMid:18048580
9. S. A. Mandel, T. Amit, O. Weinreb, L. Reznichenko and M. B. Youdim: Simultaneous manipulation of multiple brain targets by green tea catechins: a potential neuroprotective strategy for Alzheimer and Parkinson diseases. CNS Neurosci Ther, 14(4), 352-65 (2008)
doi:10.1111/j.1755-5949.2008.00060.x
10. M. M. Abd El Mohsen, G. Kuhnle, A. R. Rechner, H. Schroeter, S. Rose, P. Jenner and C. A. Rice-Evans: Uptake and metabolism of epicatechin and its access to the brain after oral ingestion. Free Radic Biol Med, 33(12), 1693-702 (2002)
doi:10.1016/S0891-5849(02)01137-1
11. L. C. Lin, M. N. Wang, T. Y. Tseng, J. S. Sung and T. H. Tsai: Pharmacokinetics of (-)-epigallocatechin-3-gallate in conscious and freely moving rats and its brain regional distribution. J Agric Food Chem, 55(4), 1517-24 (2007)
doi:10.1021/jf062816a
PMid:17256961
12. M. Suganuma, S. Okabe, M. Oniyama, Y. Tada, H. Ito and H. Fujiki: Wide distribution of (3H)(-)-epigallocatechin gallate, a cancer preventive tea polyphenol, in mouse tissue. Carcinogenesis, 19(10), 1771-6. (1998)
doi:10.1093/carcin/19.10.1771
PMid:9806157
13. K. A. Jellinger: Recent developments in the pathology of Parkinson's disease. J Neural Transm Suppl, 62, 347-76 (2002)
PMid:12456078
14. S. Mandel, E. Grunblatt, P. Riederer, M. Gerlach, Y. Levites and M. B. H. Youdim: Neuroprotective Strategies in Parkinson's disease: An Update on Progress. CNS Drugs, 17(10), 729-762 (2003)
doi:10.2165/00023210-200317100-00004
PMid:12873156
15. M. Gerlach, K. L. Double, D. Ben-Shachar, L. Zecca, M. B. Youdim and P. Riederer: Neuromelanin and its interaction with iron as a potential risk factor for dopaminergic neurodegeneration underlying Parkinson's disease. Neurotox Res, 5(1-2), 35-44 (2003)
doi:10.1007/BF03033371
PMid:12832223
16. D. J. Selkoe and D. Schenk: ALZHEIMER'S DISEASE: Molecular Understanding Predicts Amyloid-Based Therapeutics. Annu Rev Pharmacol Toxicol, 43, 545-84 (2003)
doi:10.1146/annurev.pharmtox.43.100901.140248
PMid:12415125
17. P. Riederer, E. Sofic, W. D. Rausch, B. Schmidt, G. P. Reynolds, K. Jellinger and M. B. H. Youdim: Transition metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains. J Neurochem, 52(2), 515-520 (1989)
doi:10.1111/j.1471-4159.1989.tb09150.x
PMid:2911028
18. S. Fahn and G. Cohen: The oxidant stress hypothesis in Parkinson's disease: evidence supporting it. Ann Neurol, 32(6), 804-12 (1992)
doi:10.1002/ana.410320616
PMid:1471873
19. D. Berg, M. Gerlach, M. B. H. Youdim, K. L. Double, L. Zecca, P. Riederer and G. Becker: Brain iron pathways and their relevance to Parkinson's disease. J Neurochem, 79(2), 225-236 (2001)
doi:10.1046/j.1471-4159.2001.00608.x
20. N. Khan and H. Mukhtar: Tea polyphenols for health promotion. Life Sci, 81(7), 519-33 (2007)
doi:10.1016/j.lfs.2007.06.011
PMid:17655876
21. J. V. Higdon and B. Frei: Tea catechins and polyphenols: health effects, metabolism, and antioxidant functions. Crit Rev Food Sci Nutr, 43(1), 89-143 (2003)
doi:10.1080/10408690390826464
PMid:12587987
22. S. Kuriyama, T. Shimazu, K. Ohmori, N. Kikuchi, N. Nakaya, Y. Nishino, Y. Tsubono and I. Tsuji: Green tea consumption and mortality due to cardiovascular disease, cancer, and all causes in Japan: the Ohsaki study. Jama, 296(10), 1255-65 (2006)
doi:10.1001/jama.296.10.1255
PMid:16968850
23. C. Li, A. Allen, J. Kwagh, N. M. Doliba, W. Qin, H. Najafi, H. W. Collins, F. M. Matschinsky, C. A. Stanley and T. J. Smith: Green tea polyphenols modulate insulin secretion by inhibiting glutamate dehydrogenase. J Biol Chem, 281(15), 10214-21 (2006)
doi:10.1074/jbc.M512792200
PMid:16476731
24. R. A. Anderson and M. M. Polansky: Tea enhances insulin activity. J Agric Food Chem, 50(24), 7182-6 (2002)
doi:10.1021/jf020514c
PMid:12428980
25. M. E. Waltner-Law, X. L. Wang, B. K. Law, R. K. Hall, M. Nawano and D. K. Granner: Epigallocatechin gallate, a constituent of green tea, represses hepatic glucose production. J Biol Chem, 277(38), 34933-40 (2002)
doi:10.1074/jbc.M204672200
PMid:12118006
26. S. Kuriyama, A. Hozawa, K. Ohmori, T. Shimazu, T. Matsui, S. Ebihara, S. Awata, R. Nagatomi, H. Arai and I. Tsuji: Green tea consumption and cognitive function: a cross-sectional study from the Tsurugaya Project 1. Am J Clin Nutr, 83(2), 355-61 (2006)
PMid:16469995
27. T. P. Ng, L. Feng, M. Niti, E. H. Kua and K. B. Yap: Tea consumption and cognitive impairment and decline in older Chinese adults. Am J Clin Nutr, 88(1), 224-31 (2008)
PMid:18614745
28. C. Q. Huang, B. R. Dong, Y. L. Zhang, H. M. Wu and Q. X. Liu: Association of cognitive impairment with smoking, alcohol consumption, tea consumption, and exercise among Chinese nonagenarians/centenarians. Cogn Behav Neurol, 22(3), 190-6 (2009)
doi:10.1097/WNN.0b013e3181b2790b
PMid:19741330
29. H. Checkoway, K. Powers, T. Smith-Weller, G. M. Franklin, W. T. Longstreth, Jr. and P. D. Swanson: Parkinson's disease risks associated with cigarette smoking, alcohol consumption, and caffeine intake. Am J Epidemiol, 155(8), 732-8. (2002)
doi:10.1093/aje/155.8.732
PMid:11943691
30. G. Hu, S. Bidel, P. Jousilahti, R. Antikainen and J. Tuomilehto: Coffee and tea consumption and the risk of Parkinson's disease. Mov Disord, 22, 2242-8 (2007)
doi:10.1002/mds.21706
PMid:17712848
31. L. C. Tan, W. P. Koh, J. M. Yuan, R. Wang, W. L. Au, J. H. Tan, E. K. Tan and M. C. Yu: Differential effects of black versus green tea on risk of Parkinson's disease in the Singapore Chinese Health Study. Am J Epidemiol, 167(5), 553-60 (2008)
doi:10.1093/aje/kwm338
PMid:18156141 PMCid:2737529
32. B. Kandinov, N. Giladi and A. D. Korczyn: Smoking and tea consumption delay onset of Parkinson's disease. Parkinsonism Relat Disord, 15(1), 41-6 (2009)
doi:10.1016/j.parkreldis.2008.02.011
33. C. W. Olanow, R. A. Hauser, J. Jankovic, W. Langston, A. Lang, W. Poewe, E. Tolosa, F. Stocchi, E. Melamed, E. Eyal and O. Rascol: A randomized, double-blind, placebo-controlled, delayed start study to assess rasagiline as a disease modifying therapy in Parkinson's disease (the ADAGIO study): rationale, design, and baseline characteristics. Mov Disord, 23(15), 2194-201 (2008)
doi:10.1002/mds.22218
PMid:18932271
34. C. W. Olanow, O. Rascol, R. Hauser, P. D. Feigin, J. Jankovic, A. Lang, W. Langston, E. Melamed, W. Poewe, F. Stocchi and E. Tolosa: A double-blind, delayed-start trial of rasagiline in Parkinson's disease. N Engl J Med, 361(13), 1268-78 (2009)
doi:10.1056/NEJMoa0809335
PMid:19776408
35. P. Chan, Z. Qin, Z. Zheng, L. Zhang, X. Fang, F. Sun, Z. Gu, S. Chen, J. Ma, C. Meng, J. W. Langston and C. M. Tanner: A Randomized, Double-Blind, Placebo Controlled, Delayed Start Study to Assess Safety, Tolerability and Efficacy of Green Tea Polyphenols in Parkinson's Disease. XVIII WFN World Congress on Parkinson's Disease and Related Disorders" Miami Beach, FL, USA, December 13-16, 2009 (2009)
36. J. P. Spencer: Food for thought: the role of dietary flavonoids in enhancing human memory, learning and neuro-cognitive performance. Proc Nutr Soc, 67(2), 238-52 (2008)
doi:10.1017/S0029665108007088
PMid:18412998
37. M. V. Kumari, T. Yoneda and M. Hiramatsu: Effect of "beta CATECHIN" on the life span of senescence accelerated mice (SAM-P8 strain). Biochem Mol Biol Int, 41(5), 1005-11 (1997)
PMid:9137832
38. Q. Li, H. F. Zhao, Z. F. Zhang, Z. G. Liu, X. R. Pei, J. B. Wang and Y. Li: Long-term green tea catechin administration prevents spatial learning and memory impairment in senescence-accelerated mouse prone-8 mice by decreasing Abeta1-42 oligomers and upregulating synaptic plasticity-related proteins in the hippocampus. Neuroscience, 163(3), 741-9 (2009)
doi:10.1016/j.neuroscience.2009.07.014
PMid:19596052
39. Q. Li, H. F. Zhao, Z. F. Zhang, Z. G. Liu, X. R. Pei, J. B. Wang, M. Y. Cai and Y. Li: Long-term administration of green tea catechins prevents age-related spatial learning and memory decline in C57BL/6 J mice by regulating hippocampal cyclic amp-response element binding protein signaling cascade. Neuroscience, 159(4), 1208-15 (2009)
doi:10.1016/j.neuroscience.2009.02.008
PMid:19409206
40. M. Assuncao, M. J. Santos-Marques, F. Carvalho, N. V. Lukoyanov and J. P. Andrade: Chronic green tea consumption prevents age-related changes in rat hippocampal formation. Neurobiol Aging, doi:10.1016/j.neurobiolaging.2009.03.016 (2009)
PMid:19411127
41. M. He, L. Zhao, M. J. Wei, W. F. Yao, H. S. Zhao and F. J. Chen: Neuroprotective effects of (-)-epigallocatechin-3-gallate on aging mice induced by D-galactose. Biol Pharm Bull, 32(1), 55-60 (2009)
doi:10.1248/bpb.32.55
42. L. Zhang, G. Jie, J. Zhang and B. Zhao: Significant longevity-extending effects of EGCG on Caenorhabditis elegans under stress. Free Radic Biol Med, 46(3), 414-21 (2009)
doi:10.1016/j.freeradbiomed.2008.10.041
PMid:19061950
43. S. Lee, S. Suh and S. Kim: Protective effects of the green tea polyphenol (-)-epigallocatechin gallate against hippocampal neuronal damage after transient global ischemia in gerbils. Neurosci Let, 287(3), 191-4 (2000)
doi:10.1016/S0304-3940(00)01159-9
44. B. A. Sutherland, O. M. Shaw, A. N. Clarkson, D. M. Jackson, I. A. Sammut and I. Appleton: Neuroprotective effects of (-)-epigallocatechin gallate after hypoxia-ischemia-induced brain damage: novel mechanisms of action. Faseb J, 19(2), 258-60 (2005)
PMid:15569775
45. O. Aktas, T. Prozorovski, A. Smorodchenko, N. E. Savaskan, R. Lauster, P. M. Kloetzel, C. Infante-Duarte, S. Brocke and F. Zipp: Green tea epigallocatechin-3-gallate mediates T cellular NF-kappa B inhibition and exerts neuroprotection in autoimmune encephalomyelitis. Journal of Immunol, 173(9), 5794-800 (2004)
PMid:15494532
46. J. W. Park, J. S. Hong, K. S. Lee, H. Y. Kim, J. J. Lee and S. R. Lee: Green tea polyphenol (-)-epigallocatechin gallate reduces matrix metalloproteinase-9 activity following transient focal cerebral ischemia. J Nutr Biochem, 21, 1038-44 (2009)
doi:10.1016/j.jnutbio.2009.08.009
PMid:19962294
47. S. H. Koh, S. M. Lee, H. Y. Kim, K. Y. Lee, Y. J. Lee, H. T. Kim, J. Kim, M. H. Kim, M. S. Hwang, C. Song, K. W. Yang, K. W. Lee, S. H. Kim and O. H. Kim: The effect of epigallocatechin gallate on suppressing disease progression of ALS model mice. Neurosci Lett, 395(2), 103-7 (2006)
doi:10.1016/j.neulet.2005.10.056
PMid:16356650
48. Y. Levites, O. Weinreb, G. Maor, M. B. H. Youdim and S. Mandel: Green tea polyphenol (-)- Epigallocatechin-3-gallate prevents N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurodegeneration. J Neurochem, 78, 1073-1082 (2001)
doi:10.1046/j.1471-4159.2001.00490.x
PMid:11553681
49. R. K. Chaturvedi, S. Shukla, K. Seth, S. Chauhan, C. Sinha, Y. Shukla and A. K. Agrawal: Neuroprotective and neurorescue effect of black tea extract in 6-hydroxydopamine-lesioned rat model of Parkinson's disease. Neurobiol Dis, 22(2), 421-34 (2006)
doi:10.1016/j.nbd.2005.12.008
PMid:16480889
50. L. Reznichenko, L. Kalfon, T. Amit, M. B. Youdim and S. A. Mandel: Low dosage of Rasagiline and epigallocatechin gallate synergistically restored the nigrostriatal axis in MPTP-induced parkinsonism. Neurodegener Dis, 7(4), 219-31 (2010)
doi:10.1159/000265946
PMid:20197647
51. A. M. Haque, M. Hashimoto, M. Katakura, Y. Tanabe, Y. Hara and O. Shido: Long-term administration of green tea catechins improves spatial cognition learning ability in rats. J Nutr, 136(4), 1043-7 (2006)
PMid:16549472
52. A. M. Haque, M. Hashimoto, M. Katakura, Y. Hara and O. Shido: Green tea catechins prevent cognitive deficits caused by Abeta(1-40) in rats. J Nutr Biochem, 19, 619-26 (2008)
doi:10.1016/j.jnutbio.2007.08.008
PMid:18280729
53. J. W. Lee, Y. K. Lee, J. O. Ban, T. Y. Ha, Y. P. Yun, S. B. Han, K. W. Oh and J. T. Hong: Green tea (-)-epigallocatechin-3-gallate inhibits beta-amyloid-induced cognitive dysfunction through modification of secretase activity via inhibition of ERK and NF-kappaB pathways in mice. J Nutr, 139(10), 1987-93 (2009)
doi:10.3945/jn.109.109785
PMid:19656855
54. K. Rezai-Zadeh, D. Shytle, N. Sun, T. Mori, H. Hou, D. Jeanniton, J. Ehrhart, K. Townsend, J. Zeng, D. Morgan, J. Hardy, T. Town and J. Tan: Green tea epigallocatechin-3-gallate (EGCG) modulates amyloid precursor protein cleavage and reduces cerebral amyloidosis in Alzheimer transgenic mice. J Neurosci, 25(38), 8807-14 (2005)
doi:10.1523/JNEUROSCI.1521-05.2005
PMid:16177050
55. K. Rezai-Zadeh, G. W. Arendash, H. Hou, F. Fernandez, M. Jensen, M. Runfeldt, R. D. Shytle and J. Tan: Green tea epigallocatechin-3-gallate (EGCG) reduces beta-amyloid mediated cognitive impairment and modulates tau pathology in Alzheimer transgenic mice. Brain Res, 1214, 177-87 (2008)
doi:10.1016/j.brainres.2008.02.107
PMid:18457818
56. Y. K. Lee, D. Y. Yuk, J. W. Lee, S. Y. Lee, T. Y. Ha, K. W. Oh, Y. P. Yun and J. T. Hong: (-)-Epigallocatechin-3-gallate prevents lipopolysaccharide-induced elevation of beta-amyloid generation and memory deficiency. Brain Res, 1250, 164-74 (2009)
doi:10.1016/j.brainres.2008.10.012
57. B. Giunta, D. Obregon, H. Hou, J. Zeng, N. Sun, V. Nikolic, J. Ehrhart, D. Shytle, F. Fernandez and J. Tan: EGCG mitigates neurotoxicity mediated by HIV-1 proteins gp120 and Tat in the presence of IFN-gamma: role of JAK/STAT1 signaling and implications for HIV-associated dementia. Brain Res, 1123(1), 216-25 (2006)
doi:10.1016/j.brainres.2006.09.057
PMid:17078933
58. P. Kumar and A. Kumar: Protective effects of epigallocatechin gallate following 3-nitropropionic acid-induced brain damage: possible nitric oxide mechanisms. Psychopharmacology (Berl), 207(2), 257-70 (2009)
doi:10.1007/s00213-009-1652-y
PMid:19763544
59. L. D. Mercer, B. L. Kelly, M. K. Horne and P. M. Beart: Dietary polyphenols protect dopamine neurons from oxidative insults and apoptosis: investigations in primary rat mesencephalic cultures. Biochem Pharmacol, 69(2), 339-45 (2005)
doi:10.1016/j.bcp.2004.09.018
PMid:15627486
60. Y. Levites, T. Amit, M. B. H. Youdim and S. Mandel: Involvement of protein kinase C activation and cell survival/cell cycle genes in green tea polyphenol (-)-epigallocatechin-3-gallate neuroprotective action. J Biol Chem, 277(34), 30574-80 (2002)
doi:10.1074/jbc.M202832200
PMid:12058035
61. Y. T. Choi, C. H. Jung, S. R. Lee, J. H. Bae, W. K. Baek, M. H. Suh, J. Park, C. W. Park and S. I. Suh: The green tea polyphenol (-)-epigallocatechin gallate attenuates beta- amyloid-induced neurotoxicity in cultured hippocampal neurons. Life Sci, 70(5), 603-14. (2001)
doi:10.1016/S0024-3205(01)01438-2
62. S. Mandel, L. Reznichenko, T. Amit and M. B. Youdim: Green tea polyphenol (-)-epigallocatechin-3-gallate protects rat PC12 cells from apoptosis induced by serum withdrawal independent of P13-Akt pathway. Neurotox Res, 5(6), 419-24 (2003)
doi:10.1007/BF03033171
PMid:14715445
63. J. Y. Ban, S. Y. Jeon, K. Bae, K. S. Song and Y. H. Seong: Catechin and epicatechin from Smilacis chinae rhizome protect cultured rat cortical neurons against amyloid beta protein (25-35)-induced neurotoxicity through inhibition of cytosolic calcium elevation. Life Sci, 79(24), 2251-9 (2006)
doi:10.1016/j.lfs.2006.07.021
PMid:16978655
64. L. Reznichenko, T. Amit, M. B. Youdim and S. Mandel: Green tea polyphenol (-)-epigallocatechin-3-gallate induces neurorescue of long-term serum-deprived PC12 cells and promotes neurite outgrowth. J Neurochem, 93(5), 1157-67 (2005)
doi:10.1111/j.1471-4159.2005.03085.x
PMid:15934936
65. O. Weinreb, T. Amit and M. B. Youdim: A novel approach of proteomics and transcriptomics to study the mechanism of action of the antioxidant-iron chelator green tea polyphenol (-)-epigallocatechin-3-gallate. Free Radic Biol Med, 43(4), 546-56 (2007)
doi:10.1016/j.freeradbiomed.2007.05.011
PMid:17640565
66. O. Weinreb, T. Amit and M. B. Youdim: The application of proteomics for studying the neurorescue activity of the polyphenol (-)-epigallocatechin-3-gallate. Arch Biochem Biophys, 476, 152-60 (2008)
doi:10.1016/j.abb.2008.01.004
PMid:18211800
67. L. Zecca, M. B. Youdim, P. Riederer, J. R. Connor and R. R. Crichton: Iron, brain ageing and neurodegenerative disorders. Nat Rev Neurosci, 5(11), 863-73 (2004)
doi:10.1038/nrn1537
PMid:15496864
68. M. Gerlach, K. L. Double, M. B. Youdim and P. Riederer: Potential sources of increased iron in the substantia nigra of parkinsonian patients. J Neural Transm Suppl(70), 133-42 (2006)
PMID: 17017520
69. B. Hallgren and P. Sourander: The effect of age on the nonhemin iron in the human brain. J Neurochem, 3, 41-51 (1958)
doi:10.1111/j.1471-4159.1958.tb12607.x
PMid:13611557
70. R. R. Crichton, S. Wilmet, R. Legssyer and R. J. Ward: Molecular and cellular mechanisms of iron homeostasis and toxicity in mammalian cells. J Inorg Biochem, 91(1), 9-18 (2002)
doi:10.1016/S0162-0134(02)00461-0
71. C. J. Fowler, A. Wiberg, L. Oreland, J. Marcusson and B. Winblad: The effect of age on the activity and molecular properties of human brain monoamine oxidase. J Neural Transm, 49(1-2), 1-20 (1980)
doi:10.1007/BF01249185
PMid:7441234
72. G. Cohen: Oxidative stress, mitochondrial respiration, and Parkinson's disease. Ann N Y Acad Sci, 899, 112-20 (2000)
doi:10.1111/j.1749-6632.2000.tb06180.x
73. K. J. Reinikainen, L. Paljarvi, T. Halonen, O. Malminen, V. M. Kosma, M. Laakso and P. J. Riekkinen: Dopaminergic system and monoamine oxidase-B activity in Alzheimer's disease. Neurobiol Aging, 9(3), 245-52 (1988)
doi:10.1016/S0197-4580(88)80061-7
74. D. Berg: In vivo detection of iron and neuromelanin by transcranial sonography--a new approach for early detection of substantia nigra damage. J Neural Transm, 113(6), 775-80 (2006)
doi:10.1007/s00702-005-0447-5
PMid:16755382
75. M. A. Lovell, J. D. Robertson, W. J. Teesdale, J. L. Campbell and W. R. Markesbery: Copper, iron and zinc in Alzheimer's disease senile plaques. J Neurol Sci, 158(1), 47-52 (1998)
doi:10.1016/S0022-510X(98)00092-6
76. D. J. Pinero, J. Hu and J. R. Connor: Alterations in the interaction between iron regulatory proteins and their iron responsive element in normal and Alzheimer's diseased brains. Cell Mol Biol (Noisy-Le-Grand), 46(4), 761-76. (2000)
PMID: 10875438
77. P. Zatta, D. Drago, S. Bolognin and S. L. Sensi: Alzheimer's disease, metal ions and metal homeostatic therapy. Trends Pharmacol Sci, 30(7), 346-55 (2009)
doi:10.1016/j.tips.2009.05.002
PMid:19540003
78. O. Weinreb, T. Amit, S. A. Mandel, L. Kupershmidt and M. B. Youdim: Neuroprotective multifunctional iron chelators: from redox-sensitive process to novel therapeutic opportunities. ARS, 13(6), 919-949 (2010)
PMid: 20095867
79. H. Zheng, S. Gal, L. M. Weiner, O. Bar-Am, A. Warshawsky, M. Fridkin and M. B. Youdim: Novel multifunctional neuroprotective iron chelator-monoamine oxidase inhibitor drugs for neurodegenerative diseases: in vitro studies on antioxidant activity, prevention of lipid peroxide formation and monoamine oxidase inhibition. J Neurochem, 95(1), 68-78 (2005)
doi:10.1111/j.1471-4159.2005.03340.x
PMid:16181413
80. S. Mandel, T. Amit, O. Bar-Am and M. B. Youdim: Iron dysregulation in Alzheimer's disease: multimodal brain permeable iron chelating drugs, possessing neuroprotective-neurorescue and amyloid precursor protein-processing regulatory activities as therapeutic agents. Prog Neurobiol, 82(6), 348-60 (2007)
doi:10.1016/j.pneurobio.2007.06.001
PMid:17659826
81. D. Kaur, F. Yantiri, S. Rajagopalan, J. Kumar, J. Q. Mo, R. Boonplueang, V. Viswanath, R. Jacobs, L. Yang, M. F. Beal, D. DiMonte, I. Volitaskis, L. Ellerby, R. A. Cherny, A. I. Bush and J. K. Andersen: Genetic or pharmacological iron chelation prevents MPTP-induced neurotoxicity in vivo: a novel therapy for Parkinson's disease. Neuron, 37(6), 899-909 (2003)
doi:10.1016/S0896-6273(03)00126-0
82. D. Ben-Shachar, N. Kahana, V. Kampel, A. Warshawsky and M. B. H. Youdim: Neuroprotection by a novel brain permeable iron chelator, VK-28, against 6-hydroxydopamine lesion in rats. Neuropharmacology 46, 254-263 (2004)
doi:10.1016/j.neuropharm.2003.09.005
PMid:14680763
83. M. Kumamoto, T. Sonda, K. Nagayama and M. Tabata: Effects of pH and metal ions on antioxidative activities of catechins. Biosci Biotechnol Biochem, 65(1), 126-32 (2001)
doi:10.1271/bbb.65.126
84. S. S. Park, I. Bae and Y. J. Lee: Flavonoids-induced accumulation of hypoxia-inducible factor (HIF)-1alpha/2alpha is mediated through chelation of iron. J Cell Biochem, 103(6), 1989-98 (2008)
doi:10.1002/jcb.21588
PMid:17973296
85. N. R. Perron, J. N. Hodges, M. Jenkins and J. L. Brumaghim: Predicting how polyphenol antioxidants prevent DNA damage by binding to iron. Inorg Chem, 47(14), 6153-61 (2008)
doi:10.1021/ic7022727
PMid:18553907
86. N. R. Perron, H. C. Wang, S. N. Deguire, M. Jenkins, M. Lawson and J. L. Brumaghim: Kinetics of iron oxidation upon polyphenol binding. Dalton Trans, 39(41), 9982-7 (2010)
doi:10.1039/c0dt00752h
PMid:20871896
87. P. I. Moreira, S. L. Siedlak, G. Aliev, X. Zhu, A. D. Cash, M. A. Smith and G. Perry: Oxidative stress mechanisms and potential therapeutics in Alzheimer disease. J Neural Transm, 112(7), 921-32 (2005)
doi:10.1007/s00702-004-0242-8
PMid:15583960
88. M. A. Smith, C. A. Rottkamp, A. Nunomura, A. K. Raina and G. Perry: Oxidative stress in Alzheimer's disease. Biochim Biophys Acta, 1502(1), 139-44. (2000)
PMid:10899439
89. N. Salah, N. J. Miller, G. Paganga, L. Tijburg, G. P. Bolwell and C. Rice-Evans: Polyphenolic flavanols as scavengers of aqueous phase radicals and as chain-breaking antioxidants. Arch Biochem Biophy., 322(2), 339-346 (1995)
doi:10.1006/abbi.1995.1473
PMid:7574706
90. Y. Levites, M. B. H. Youdim, G. Maor and S. Mandel: Attenuation of 6-hydroxydopamine (6-OHDA)-induced nuclear factor-kappaB (NF-kappaB) activation and cell death by tea extracts in neuronal cultures. Biochem Pharmacol, 63(1), 21-9 (2002)
doi:10.1016/S0006-2952(01)00813-9
91. E. Skrzydlewska, A. Augustyniak, K. Michalak and R. Farbiszewski: Green tea supplementation in rats of different ages mitigates ethanol-induced changes in brain antioxidant abilities. Alcohol, 37(2), 89-98 (2005)
doi:10.1016/j.alcohol.2005.12.003
PMid:16584972
92. R. Srividhya, V. Jyothilakshmi, K. Arulmathi, V. Senthilkumaran and P. Kalaiselvi: Attenuation of senescence-induced oxidative exacerbations in aged rat brain by (-)-epigallocatechin-3-gallate. Int J Dev Neurosci, 26(2), 217-23 (2008)
doi:10.1016/j.ijdevneu.2007.12.003
PMid:18207349
93. M. Assuncao, M. J. Santos-Marques, F. Carvalho and J. P. Andrade: Green tea averts age-dependent decline of hippocampal signaling systems related to antioxidant defenses and survival. Free Radic Biol Med, 48(6), 831-8 (2010)
doi:10.1016/j.freeradbiomed.2010.01.003
PMid:20064606
94. S. M. Lin, S. W. Wang, S. C. Ho and Y. L. Tang: Protective effect of green tea (-)-epigallocatechin-3-gallate against the monoamine oxidase B enzyme activity increase in adult rat brains. Nutrition, 26(11-12), 1195-200 (2010)
doi:10.1016/j.nut.2009.11.022
PMid:20472400
95. E. A. Mazzio, N. Harris and K. F. Soliman: Food constituents attenuate monoamine oxidase activity and peroxide levels in C6 astrocyte cells. Planta Med, 64(7), 603-6 (1998)
doi:10.1055/s-2006-957530
PMid:9810264
96. J. S. Kim, J. M. Kim, J. J. O and B. S. Jeon: Inhibition of inducible nitric oxide synthase expression and cell death by (-)-epigallocatechin-3-gallate, a green tea catechin, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease. J Clin Neurosci, 17(9), 1165-8
doi:10.1016/j.jocn.2010.01.042
PMid:20541420
97. E. D. Owuor and A. N. Kong: Antioxidants and oxidants regulated signal transduction pathways. Biochem Pharmacol, 64(5-6), 765-70 (2002)
doi:10.1016/S0006-2952(02)01137-1
98. G. E. Mann, D. J. Rowlands, F. Y. Li, P. de Winter and R. C. Siow: Activation of endothelial nitric oxide synthase by dietary isoflavones: role of NO in Nrf2-mediated antioxidant gene expression. Cardiovasc Res, 75(2), 261-74 (2007)
doi:10.1016/j.cardiores.2007.04.004
PMid:17498676
99. A. I. Bush: The metallobiology of Alzheimer's disease. Trends Neurosci, 26(4), 207-14 (2003)
doi:10.1016/S0166-2236(03)00067-5
100. R. J. Castellani, P. I. Moreira, G. Liu, J. Dobson, G. Perry, M. A. Smith and X. Zhu: Iron: the Redox-active center of oxidative stress in Alzheimer disease. Neurochem Res, 32(10), 1640-5 (2007)
doi:10.1007/s11064-007-9360-7
PMid:17508283
101. C. S. Atwood, R. C. Scarpa, X. Huang, R. D. Moir, W. D. Jones, D. P. Fairlie, R. E. Tanzi and A. I. Bush: Characterization of copper interactions with alzheimer amyloid beta peptides: identification of an attomolar-affinity copper binding site on amyloid beta1-42. J Neurochem, 75(3), 1219-33. (2000)
doi:10.1046/j.1471-4159.2000.0751219.x
102. C. A. Rottkamp, A. K. Raina, X. Zhu, E. Gaier, A. I. Bush, C. S. Atwood, M. Chevion, G. Perry and M. A. Smith: Redox-active iron mediates amyloid-beta toxicity. Free Radic Biol Med, 30(4), 447-50. (2001)
doi:10.1016/S0891-5849(00)00494-9
103. S. Turnbull, B. J. Tabner, O. M. El-Agnaf, S. Moore, Y. Davies and D. Allsop: alpha-Synuclein implicated in Parkinson's disease catalyses the formation of hydrogen peroxide in vitro. Free Radic Biol Med, 30(10), 1163-70. (2001)
doi:10.1016/S0891-5849(01)00513-5
104. N. Ostrerova-Golts, L. Petrucelli, J. Hardy, J. M. Lee, M. Farer and B. Wolozin: The A53T alpha-synuclein mutation increases iron-dependent aggregation and toxicity. Journal of Neuroscience, 20(16), 6048-54. (2000)
PMid:10934254
105. K. Ono, Y. Yoshiike, A. Takashima, K. Hasegawa, H. Naiki and M. Yamada: Potent anti-amyloidogenic and fibril-destabilizing effects of polyphenols in vitro: implications for the prevention and therapeutics of Alzheimer's disease. J Neurochem, 87(1), 172-81 (2003)
doi:10.1046/j.1471-4159.2003.01976.x
PMid:12969264
106. K. Ono and M. Yamada: Antioxidant compounds have potent anti-fibrillogenic and fibril-destabilizing effects for alpha-synuclein fibrils in vitro. J Neurochem, 97(1), 105-15 (2006)
doi:10.1111/j.1471-4159.2006.03707.x
PMid:16524383
107. D. E. Ehrnhoefer, J. Bieschke, A. Boeddrich, M. Herbst, L. Masino, R. Lurz, S. Engemann, A. Pastore and E. E. Wanker: EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomers. Nat Struct Mol Biol, 15(6), 558-66 (2008)
doi:10.1038/nsmb.1437
108. A. R. Ladiwala, J. C. Lin, S. S. Bale, A. M. Marcelino-Cruz, M. Bhattacharya, J. S. Dordick and P. M. Tessier: Resveratrol selectively remodels soluble oligomers and fibrils of amyloid Abeta into off-pathway conformers. J Biol Chem, 285(31), 24228-37
doi:10.1074/jbc.M110.133108
PMid:20511235
109. D. J. Selkoe: Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior. Behav Brain Res, 192(1), 106-13 (2008)
doi:10.1016/j.bbr.2008.02.016
PMid:18359102 PMCid:2601528
110. M. Periquet, T. Fulga, L. Myllykangas, M. G. Schlossmacher and M. B. Feany: Aggregated alpha-synuclein mediates dopaminergic neurotoxicity in vivo. J Neurosci, 27(12), 3338-46 (2007)
doi:10.1523/JNEUROSCI.0285-07.2007
PMid:17376994
111. J. Bieschke, J. Russ, R. P. Friedrich, D. E. Ehrnhoefer, H. Wobst, K. Neugebauer and E. E. Wanker: EGCG remodels mature alpha-synuclein and amyloid-beta fibrils and reduces cellular toxicity. Proc Natl Acad Sci U S A, 107(17), 7710-5 (2010)
doi:10.1073/pnas.0910723107
PMid:20385841 PMCid:2867908
112. S. Bastianetto, Z. X. Yao, V. Papadopoulos and R. Quirion: Neuroprotective effects of green and black teas and their catechin gallate esters against beta-amyloid-induced toxicity. Eur J Neurosci, 23(1), 55-64 (2006)
doi:10.1111/j.1460-9568.2005.04532.x
PMid:16420415
113. L. Reznichenko, T. Amit, H. Zheng, Y. Avramovich-Tirosh, M. B. Youdim, O. Weinreb and S. Mandel: Reduction of iron-regulated amyloid precursor protein and beta-amyloid peptide by (-)-epigallocatechin-3-gallate in cell cultures: implications for iron chelation in Alzheimer's disease. J Neurochem, 97(2), 527-36 (2006)
doi:10.1111/j.1471-4159.2006.03770.x
PMid:16539659
114. J. T. Rogers, J. D. Randall, C. M. Cahill, P. S. Eder, X. Huang, H. Gunshin, L. Leiter, J. McPhee, S. S. Sarang, T. Utsuki, N. H. Greig, D. K. Lahiri, R. E. Tanzi, A. I. Bush, T. Giordano and S. R. Gullans: An iron-responsive element type II in the 5'-untranslated region of the Alzheimer's amyloid precursor protein transcript. J Biol Chem, 277(47), 45518-28 (2002)
doi:10.1074/jbc.M207435200
PMid:12198135
115. S. A. Mandel, Y. Avramovich-Tirosh, L. Reznichenko, H. Zheng, O. Weinreb, T. Amit and M. B. Youdim: Multifunctional activities of green tea catechins in neuroprotection. Neurosignals, 14(1-2), 46-60 (2005)
doi:10.1159/000085385
PMid:15956814
116. A. L. Friedlich, R. E. Tanzi and J. T. Rogers: The 5'-untranslated region of Parkinson's disease alpha-synuclein messengerRNA contains a predicted iron responsive element. Mol Psychiatry, 12(3), 222-3 (2007)
doi:10.1038/sj.mp.4001937
PMid:17325711
117. C. J. Schofield and P. J. Ratcliffe: Oxygen sensing by HIF hydroxylases. Nat Rev Mol Cell Biol, 5(5), 343-54 (2004)
doi:10.1038/nrm1366
PMid:15122348
118. A. Giaccia, B. G. Siim and R. S. Johnson: HIF-1 as a target for drug development. Nat Rev Drug Discov, 2(10), 803-11 (2003)
doi:10.1038/nrd1199
PMid:14526383
119. D. W. Lee, S. Rajagopalan, A. Siddiq, R. Gwiazda, L. Yang, M. F. Beal, R. R. Ratan and J. K. Andersen: Inhibition of prolyl hydroxylase protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity: model for the potential involvement of the hypoxia-inducible factor pathway in Parkinson disease. J Biol Chem, 284(42), 29065-76 (2009)
doi:10.1074/jbc.M109.000638
PMid:19679656 PMCid:2781452
120. L. Kupershmidt, O. Weinreb, T. Amit, S. Mandel, M. T. Carri and M. B. Youdim: Neuroprotective and neuritogenic activities of novel multimodal iron-chelating drugs in motor-neuron-like NSC-34 cells and transgenic mouse model of amyotrophic lateral sclerosis. Faseb J, 23(11), 3766-79 (2009)
doi:10.1096/fj.09-130047
PMid:19638399
121. A. Siddiq, L. R. Aminova, C. M. Troy, K. Suh, Z. Messer, G. L. Semenza and R. R. Ratan: Selective inhibition of hypoxia-inducible factor (HIF) prolyl-hydroxylase 1 mediates neuroprotection against normoxic oxidative death via HIF- and CREB-independent pathways. J Neurosci, 29(27), 8828-38 (2009)
doi:10.1523/JNEUROSCI.1779-09.2009
PMid:19587290
122. G. Agullo, L. Gamet-Payrastre, S. Manenti, C. Viala, C. Remesy, H. Chap and B. Payrastre: Relationship between flavonoid structure and inhibition of phosphatidylinositol 3-kinase: a comparison with tyrosine kinase and protein kinase C inhibition. Biochem Pharmacol, 53(11), 1649-57 (1997)
doi:10.1016/S0006-2952(97)82453-7
123. W. J. Wilson and L. Poellinger: The dietary flavonoid quercetin modulates HIF-1 alpha activity in endothelial cells. Biochem Biophys Res Commun, 293(1), 446-50 (2002)
doi:10.1016/S0006-291X(02)00244-9
124. A. Triantafyllou, P. Liakos, A. Tsakalof, G. Chachami, E. Paraskeva, P. A. Molyvdas, E. Georgatsou, G. Simos and S. Bonanou: The flavonoid quercetin induces hypoxia-inducible factor-1alpha (HIF-1alpha) and inhibits cell proliferation by depleting intracellular iron. Free Radic Res, 41(3), 342-56 (2007)
doi:10.1080/10715760601055324
PMid:17364964
125. Z. Li, K. Ya, W. Xiao-Mei, Y. Lei, L. Yang and Q. Z. Ming: Ginkgolides protect PC12 cells against hypoxia-induced injury by p42/p44 MAPK pathway-dependent upregulation of HIF-1alpha expression and HIF-1DNA-binding activity. J Cell Biochem, 103(2), 564-75 (2008)
doi:10.1002/jcb.21427
PMid:17647269
126. A. Triantafyllou, I. Mylonis, G. Simos, S. Bonanou and A. Tsakalof: Flavonoids induce HIF-1alpha but impair its nuclear accumulation and activity. Free Radic Biol Med, 44(4), 657-70 (2008)
doi:10.1016/j.freeradbiomed.2007.10.050
PMid:18061585
127. H. Jeon, H. Kim, D. Choi, D. Kim, S. Y. Park, Y. J. Kim, Y. M. Kim and Y. Jung: Quercetin activates an angiogenic pathway, hypoxia inducible factor (HIF)-1-vascular endothelial growth factor, by inhibiting HIF-prolyl hydroxylase: a structural analysis of quercetin for inhibiting HIF-prolyl hydroxylase. Mol Pharmacol, 71(6), 1676-84 (2007)
doi:10.1124/mol.107.034041
PMid:17377063
128. R. Thomas and M. H. Kim: Epigallocatechin gallate inhibits HIF-1alpha degradation in prostate cancer cells. Biochem Biophys Res Commun, 334(2), 543-8 (2005)
doi:10.1016/j.bbrc.2005.06.114
PMid:16005427
129. Y. D. Zhou, Y. P. Kim, X. C. Li, S. R. Baerson, A. K. Agarwal, T. W. Hodges, D. Ferreira and D. G. Nagle: Hypoxia-inducible factor-1 activation by (-)-epicatechin gallate: potential adverse effects of cancer chemoprevention with high-dose green tea extracts. J Nat Prod, 67(12), 2063-9 (2004)
doi:10.1021/np040140c
PMid:15620252 PMCid:2914555
130. T. A. Rouault: The role of iron regulatory proteins in mammalian iron homeostasis and disease. Nat Chem Biol, 2(8), 406-14 (2006)
doi:10.1038/nchembio807
PMid:16850017
131. D. R. Mole: Iron homeostasis and its interaction with prolyl hydroxylases. Antioxid Redox Signal, 12(4), 445-58 (2010)
doi:10.1089/ars.2009.2790
PMid:19650690
132. E. S. Hanson and E. A. Leibold: Regulation of the iron regulatory proteins by reactive nitrogen and oxygen species. Gene Expr, 7(4-6), 367-76 (1999)
PMid:10440237
133. J. Wang, G. Chen, M. Muckenthaler, B. Galy, M. W. Hentze and K. Pantopoulos: Iron-mediated degradation of IRP2, an unexpected pathway involving a 2-oxoglutarate-dependent oxygenase activity. Mol Cell Biol, 24(3), 954-65 (2004)
doi:10.1128/MCB.24.3.954-965.2004
PMid:14729944 PMCid:321427
134. L. Kalfon, M. B. Youdim and S. A. Mandel: Green tea polyphenol (-) -epigallocatechin-3-gallate promotes the rapid protein kinase C- and proteasome-mediated degradation of Bad: implications for neuroprotection. J Neurochem, 100(4), 992-1002 (2007)
doi:10.1111/j.1471-4159.2006.04265.x
PMid:17156130
135. E. Berra, M. M. Municio, L. Sanz, S. Frutos, M. T. Diaz-Meco and J. Moscat: Positioning atypical protein kinase C isoforms in the UV-induced apoptotic signaling cascade. Mol Cell Biol, 17(8), 4346-54. (1997)
PMid:9234692
136. J. P. Durkin, R. Tremblay, B. Chakravarthy, G. Mealing, P. Morley, D. Small and D. Song: Evidence that the early loss of membrane protein kinase C is a necessary step in the excitatory amino acid-induced death of primary cortical neurons. J Neurochem, 68(4), 1400-12. (1997)
doi:10.1046/j.1471-4159.1997.68041400.x
137. M. R. Vianna, D. M. Barros, T. Silva, H. Choi, C. Madche, C. Rodrigues, J. H. Medina and I. Izquierdo: Pharmacological demonstration of the differential involvement of protein kinase C isoforms in short- and long-term memory formation and retrieval of one-trial avoidance in rats. Psychopharmacology (Berl), 150(1), 77-84 (2000)
doi:10.1007/s002130000396
PMid:10867979
138. C. Lange-Asschenfeldt, A. P. Raval, K. R. Dave, D. Mochly-Rosen, T. J. Sick and M. A. Perez-Pinzon: Epsilon protein kinase C mediated ischemic tolerance requires activation of the extracellular regulated kinase pathway in the organotypic hippocampal slice. J Cereb Blood Flow Metab, 24(6), 636-45 (2004)
doi:10.1097/01.WCB.0000121235.42748.BF
139. M. Cordey, U. Gundimeda, R. Gopalakrishna and C. J. Pike: Estrogen activates protein kinase C in neurons: role in neuroprotection. J Neurochem, 84(6), 1340-8 (2003)
doi:10.1046/j.1471-4159.2003.01631.x
PMid:12614334
140. Y. S. Han, W. H. Zheng, S. Bastianetto, J. G. Chabot and R. Quirion: Neuroprotective effects of resveratrol against beta-amyloid-induced neurotoxicity in rat hippocampal neurons: involvement of protein kinase C. Br J Pharmacol, 141(6), 997-1005 (2004)
doi:10.1038/sj.bjp.0705688
PMid:15028639 PMCid:1574264
141. S. Kumazawa, K. Kajiya, A. Naito, H. Saito, S. Tuzi, M. Tanio, M. Suzuki, F. Nanjo, E. Suzuki and T. Nakayama: Direct evidence of interaction of a green tea polyphenol, epigallocatechin gallate, with lipid bilayers by solid-state Nuclear Magnetic Resonance. Biosci Biotechnol Biochem, 68(8), 1743-7 (2004)
doi:10.1271/bbb.68.1743
142. K. Kajiya, S. Kumazawa, A. Naito and T. Nakayama: Solid-state NMR analysis of the orientation and dynamics of epigallocatechin gallate, a green tea polyphenol, incorporated into lipid bilayers. Magn Reson Chem, 46(2), 174-7 (2008)
doi:10.1002/mrc.2157
PMid:18098154
143. H. Saito, R. Tabeta, M. Kodama, C. Nagata and Y. Sato: Direct evidence of incorporation of 12-O-(20-2H1)tetradecanoylphorbol-13-acetate into artificial membranes as determined by deuterium magnetic resonance. Cancer Lett, 22(1), 65-9 (1984)
doi:10.1016/0304-3835(84)90044-2
144. Y. A. Mahmmoud: Modulation of protein kinase C by curcumin; inhibition and activation switched by calcium ions. Br J Pharmacol, 150(2), 200-8 (2007)
doi:10.1038/sj.bjp.0706970
PMid:17160011 PMCid:2042896
145. A. Majhi, G. M. Rahman, S. Panchal and J. Das: Binding of curcumin and its long chain derivatives to the activator binding domain of novel protein kinase C. Bioorg Med Chem, 18(4), 1591-8 (2010)
doi:10.1016/j.bmc.2009.12.075
146. H. Schroeter, P. Bahia, J. P. Spencer, O. Sheppard, M. Rattray, E. Cadenas, C. Rice-Evans and R. J. Williams: (-)Epicatechin stimulates ERK-dependent cyclic AMP response element activity and up-regulates GluR2 in cortical neurons. J Neurochem, 101(6), 1596-606 (2007)
doi:10.1111/j.1471-4159.2006.04434.x
PMid:17298385
147. Y. Levites, T. Amit, S. Mandel and M. B. H. Youdim: Neuroprotection and Neurorescue Against Amyloid beta Toxicity and PKC-Dependent Release of Non-Amyloidogenic Soluble Precusor Protein by Green Tea Polyphenol (-)-Epigallocatechin-3-gallate. FASEB J, 17((8)), 952-4 (2003)
PMid:12670874
148. S. Y. Kim, B. H. Ahn, J. Kim, Y. S. Bae, J. Y. Kwak, G. Min, T. K. Kwon, J. S. Chang, Y. H. Lee, S. H. Yoon and S. Min do: Phospholipase C, protein kinase C, Ca2+/calmodulin-dependent protein kinase II, and redox state are involved in epigallocatechin gallate-induced phospholipase D activation in human astroglioma cells. Eur J Biochem, 271(17), 3470-80 (2004)
doi:10.1111/j.0014-2956.2004.04242.x
PMid:15317582
149. S. Mandel, G. Maor and M. B. Youdim: Iron and alpha-synuclein in the substantia nigra of MPTP-treated mice: effect of neuroprotective drugs R-apomorphine and green tea polyphenol (-)-epigallocatechin-3-gallate. J Mol Neurosci, 24(3), 401-16 (2004)
doi:10.1385/JMN:24:3:401
150. S. Shimizu, M. Narita and Y. Tsujimoto: Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature, 399(6735), 483-7 (1999)
doi:10.1038/20959
PMid:10365962
151. R. Srividhya, K. Zarkovic, M. Stroser, G. Waeg, N. Zarkovic and P. Kalaiselvi: Mitochondrial alterations in aging rat brain: effective role of (-)-epigallo catechin gallate. Int J Dev Neurosci, 27(3), 223-31 (2009)
doi:10.1016/j.ijdevneu.2009.01.003
PMid:19429387
152. E. K. Schroeder, N. A. Kelsey, J. Doyle, E. Breed, R. J. Bouchard, A. Loucks, A. Harbison and D. A. Linseman: Green tea epigallocatechin 3-gallate accumulates in mitochondria and displays a selective anti-apoptotic effect against inducers of mitochondrial oxidative stress in neurons. Antioxid Redox Signal, 11, 469-80 (2008)
doi:10.1089/ars.2008.2215
PMid:18754708
153. K. S. Panickar, M. M. Polansky and R. A. Anderson: Green tea polyphenols attenuate glial swelling and mitochondrial dysfunction following oxygen-glucose deprivation in cultures. Nutr Neurosci, 12(3), 105-13 (2009)
doi:10.1179/147683009X423300
PMid:19356313
154. D. J. Selkoe: The molecular pathology of Alzheimer's disease. Neuron, 6(4), 487-98. (1991)
doi:10.1016/0896-6273(91)90052-2
155. M. P. Mattson, S. W. Barger, K. Furukawa, A. J. Bruce, T. Wyss-Coray, R. J. Mark and L. Mucke: Cellular signaling roles of TGF beta, TNF alpha and beta APP in brain injury responses and Alzheimer's disease. Brain Res Rev, 23(1-2), 47-61 (1997)
doi:10.1016/S0165-0173(96)00014-8
156. D. H. Small, V. Nurcombe, G. Reed, H. Clarris, R. Moir, K. Beyreuther and C. L. Masters: A heparin-binding domain in the amyloid protein precursor of Alzheimer's disease is involved in the regulation of neurite outgrowth. J Neurosci, 14(4), 2117-27. (1994)
PMid:8158260
157. T. Morimoto, I. Ohsawa, C. Takamura, M. Ishiguro and S. Kohsaka: Involvement of amyloid precursor protein in functional synapse formation in cultured hippocampal neurons. J Neurosci Res, 51(2), 185-95. (1998)
3.0.CO;2-9" target=_blankdoi:10.1002/(SICI)1097-4547(19980115)51:2<185::AID-JNR7>3.0.CO;2-9
158. D. F. Obregon, K. Rezai-Zadeh, Y. Bai, N. Sun, H. Hou, J. Ehrhart, J. Zeng, T. Mori, G. W. Arendash, D. Shytle, T. Town and J. Tan: ADAM10 activation is required for green tea (-)-epigallocatechin-3-gallate-induced alpha-secretase cleavage of amyloid precursor protein. J Biol Chem, 281(24), 16419-27 (2006)
doi:10.1074/jbc.M600617200
PMid:16624814
159. A. Smith, B. Giunta, P. C. Bickford, M. Fountain, J. Tan and R. D. Shytle: Nanolipidic particles improve the bioavailability and alpha-secretase inducing ability of epigallocatechin-3-gallate (EGCG) for the treatment of Alzheimer's disease. Int J Pharm, 389(1-2), 207-12 (2010)
doi:10.1016/j.ijpharm.2010.01.012
PMid:20083179
160. D. S. Choi, D. Wang, G. Q. Yu, G. Zhu, V. N. Kharazia, J. P. Paredes, W. S. Chang, J. K. Deitchman, L. Mucke and R. O. Messing: PKCepsilon increases endothelin converting enzyme activity and reduces amyloid plaque pathology in transgenic mice. Proc Natl Acad Sci U S A, 103(21), 8215-20 (2006)
doi:10.1073/pnas.0509725103
PMid:16698938 PMCid:1472455
161. A. Takeuchi, M. C. Irizarry, K. Duff, T. C. Saido, K. Hsiao Ashe, M. Hasegawa, D. M. Mann, B. T. Hyman and T. Iwatsubo: Age-related amyloid beta deposition in transgenic mice overexpressing both Alzheimer mutant presenilin 1 and amyloid beta precursor protein Swedish mutant is not associated with global neuronal loss. Am J Pathol, 157(1), 331-9 (2000)
doi:10.1016/S0002-9440(10)64544-0
162. R. Li, N. Peng, X. P. Li and W. D. Le: (-)-Epigallocatechin gallate regulates dopamine transporter internalization via protein kinase C-dependent pathway. Brain Res, 1097(1), 85-9 (2006)
doi:10.1016/j.brainres.2006.04.071
PMid:16733047
163. H. Lu, X. Meng and C. S. Yang: Enzymology of methylation of tea catechins and inhibition of catechol-O-methyltransferase by (-)-epigallocatechin gallate. Drug Metab Dispos, 31(5), 572-9 (2003)
doi:10.1124/dmd.31.5.572
PMid:12695345
164. R. K. Dagda, J. Zhu and C. T. Chu: Mitochondrial kinases in Parkinson's disease: converging insights from neurotoxin and genetic models. Mitochondrion, 9(5), 289-98 (2009)
doi:10.1016/j.mito.2009.06.001
PMid:19563915 PMCid:2748152
165. T. Satoh, D. Nakatsuka, Y. Watanabe, I. Nagata, H. Kikuchi and S. Namura: Neuroprotection by MAPK/ERK kinase inhibition with U0126 against oxidative stress in a mouse neuronal cell line and rat primary cultured cortical neurons. Neurosci Lett, 288(2), 163-6. (2000)
doi:10.1016/S0304-3940(00)01229-5
166. H. Schroeter, C. Boyd, J. P. Spencer, R. J. Williams, E. Cadenas and C. Rice-Evans: MAPK signaling in neurodegeneration: influences of flavonoids and of nitric oxide. Neurobiol Aging, 23(5), 861-80 (2002)
doi:10.1016/S0197-4580(02)00075-1
167. C. Chen, R. Yu, E. D. Owuor and A. N. Kong: Activation of antioxidant-response element (ARE), mitogen-activated protein kinases (MAPKs) and caspases by major green tea polyphenol components during cell survival and death. Arch Pharm Res, 23(6), 605-12. (2000)
doi:10.1007/BF02975249
PMid:11156183
168. S. Impey, S. R. McCorkle, H. Cha-Molstad, J. M. Dwyer, G. S. Yochum, J. M. Boss, S. McWeeney, J. J. Dunn, G. Mandel and R. H. Goodman: Defining the CREB regulon: a genome-wide analysis of transcription factor regulatory regions. Cell, 119(7), 1041-54 (2004)
doi:10.1016/S0092-8674(04)01159-6
169. A. Barco, C. H. Bailey and E. R. Kandel: Common molecular mechanisms in explicit and implicit memory. J Neurochem, 97(6), 1520-33 (2006)
doi:10.1111/j.1471-4159.2006.03870.x
PMid:16805766
170. T. I. Kim, Y. K. Lee, S. G. Park, I. S. Choi, J. O. Ban, H. K. Park, S. Y. Nam, Y. W. Yun, S. B. Han, K. W. Oh and J. T. Hong: l-Theanine, an amino acid in green tea, attenuates beta-amyloid-induced cognitive dysfunction and neurotoxicity: reduction in oxidative damage and inactivation of ERK/p38 kinase and NF-kappaB pathways. Free Radic Biol Med, 47(11), 1601-10 (2009)
doi:10.1016/j.freeradbiomed.2009.09.008
PMid:19766184
171. M. R. Farlow, M. L. Miller and V. Pejovic: Treatment options in Alzheimer's disease: maximizing benefit, managing expectations. Dement Geriatr Cogn Disord, 25(5), 408-22 (2008)
doi:10.1159/000122962
PMid:18391487
172. J. B. Standridge: Pharmacotherapeutic approaches to the treatment of Alzheimer's disease. Clin Ther, 26(5), 615-30 (2004)
doi:10.1016/S0149-2918(04)90064-1
173. J. Stoessl: Potential therapeutic targets for Parkinson's disease. Expert Opin Ther Targets, 12(4), 425-36 (2008)
doi:10.1517/14728222.12.4.425
PMid:18348679
174. A. H. Schapira, Y. Agid, P. Barone, P. Jenner, M. R. Lemke, W. Poewe, O. Rascol, H. Reichmann and E. Tolosa: Perspectives on recent advances in the understanding and treatment of Parkinson's disease. Eur J Neurol, 16(10), 1090-9 (2009)
doi:10.1111/j.1468-1331.2009.02793.x
PMid:19723294
175. U. Cornelli: Treatment of Alzheimer's disease with a cholinesterase inhibitor combined with antioxidants. Neurodegener Dis, 7(1-3), 193-202
doi:10.1159/000295663
PMid:20224285
176. R. Remington, A. Chan, J. Paskavitz and T. B. Shea: Efficacy of a vitamin/nutriceutical formulation for moderate-stage to later-stage Alzheimer's disease: a placebo-controlled pilot study. Am J Alzheimers Dis Other Demen, 24(1), 27-33 (2009)
doi:10.1177/1533317508325094
PMid:19056706
177. A. Chan, J. Paskavitz, R. Remington, S. Rasmussen and T. B. Shea: Efficacy of a vitamin/nutriceutical formulation for early-stage Alzheimer's disease: a 1-year, open-label pilot study with an 16-month caregiver extension. Am J Alzheimers Dis Other Demen, 23(6), 571-85 (2008)
doi:10.1177/1533317508325093
PMid:19047474
178. PSG: A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease. Arch Neurol, 61(4), 561-6 (2004)
doi:10.1001/archneur.61.4.561
PMid:15096406
179. Y. Sagi, S. Mandel, T. Amit and M. B. Youdim: Activation of tyrosine kinase receptor signaling pathway by rasagiline facilitates neurorescue and restoration of nigrostriatal dopamine neurons in post-MPTP-induced parkinsonism. Neurobiol Dis, 25(1), 35-44 (2007)
doi:10.1016/j.nbd.2006.07.020
PMid:17055733
180. W. Zhu, W. Xie, T. Pan, J. Jankovic, J. Li, M. B. Youdim and W. Le: Comparison of neuroprotective and neurorestorative capabilities of rasagiline and selegiline against lactacystin-induced nigrostriatal dopaminergic degeneration. J Neurochem, 105(5), 1970-8 (2008)
doi:10.1111/j.1471-4159.2008.05330.x
PMid:18399960
181. R. A. Hauser, M. F. Lew, H. I. Hurtig, W. G. Ondo, J. Wojcieszek and C. J. Fitzer-Attas: Long-term outcome of early versus delayed rasagiline treatment in early Parkinson's disease. Mov Disord, 24(4), 564-73 (2009)
doi:10.1002/mds.22402
PMid:19086083
182. C. M. Chen, J. K. Lin, S. H. Liu and S. Y. Lin-Shiau: Novel regimen through combination of memantine and tea polyphenol for neuroprotection against brain excitotoxicity. J Neurosci Res, 86(12), 2696-704 (2008)
doi:10.1002/jnr.21706
PMid:18478543
183. B. Giunta, H. Hou, Y. Zhu, J. Salemi, A. Ruscin, R. D. Shytle and J. Tan: Fish oil enhances anti-amyloidogenic properties of green tea EGCG in Tg2576 mice. Neurosci Lett, 471(3), 134-8 (2010)
doi:10.1016/j.neulet.2010.01.026
PMid:20096749
184. Q. L. Ma, F. Yang, E. R. Rosario, O. J. Ubeda, W. Beech, D. J. Gant, P. P. Chen, B. Hudspeth, C. Chen, Y. Zhao, H. V. Vinters, S. A. Frautschy and G. M. Cole: Beta-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase signaling: suppression by omega-3 fatty acids and curcumin. J Neurosci, 29(28), 9078-89 (2009)
doi:10.1523/JNEUROSCI.1071-09.2009
PMid:19605645
185. S. Acosta, J. Jernberg, C. D. Sanberg, P. R. Sanberg, B. J. Small, C. Gemma and P. C. Bickford: NT-020, a Natural Therapeutic Approach to Optimize Spatial Memory Performance and Increase Neural Progenitor Cell Proliferation and Decrease Inflammation in the Aged Rat. Rejuvenation Res (2010)
PMID: 20586644
Key Words: Green tea polyphenols, combination therapy, neuroprotection/neurorescue, hypoxia inducible factor, iron chelation, Parkinson's disease; Alzheimer's disease, Review
Send correspondence to: Silvia Alicia Mandel, Eve Topf Center for Neurodegenerative Diseases Research and Dept. of Molecular Pharmacology, Faculty of Medicine, Technion, Haifa, Israel, Tel: 972-4-8295289, Fax: 972-4-8513145, E-mail:mandel@tx.technion.ac.il